JP7486615B2 - Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis - Google Patents

Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis Download PDF

Info

Publication number
JP7486615B2
JP7486615B2 JP2022575390A JP2022575390A JP7486615B2 JP 7486615 B2 JP7486615 B2 JP 7486615B2 JP 2022575390 A JP2022575390 A JP 2022575390A JP 2022575390 A JP2022575390 A JP 2022575390A JP 7486615 B2 JP7486615 B2 JP 7486615B2
Authority
JP
Japan
Prior art keywords
nmr
ppm
compound
amino
yield
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
JP2022575390A
Other languages
Japanese (ja)
Other versions
JP2023533661A (en
Inventor
クオ，タイ－ファン
シーイェ，ポ－チュン
チェン，ミン－ロン
フ，チ－ウェイ
Original Assignee
アピカル モレキュラー バイオテック カンパニー リミテッド
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by アピカル モレキュラー バイオテック カンパニー リミテッド filed Critical アピカル モレキュラー バイオテック カンパニー リミテッド
Publication of JP2023533661A publication Critical patent/JP2023533661A/en
Application granted granted Critical
Publication of JP7486615B2 publication Critical patent/JP7486615B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
    • C07C329/02—Monothiocarbonic acids; Derivatives thereof
    • C07C329/04—Esters of monothiocarbonic acids
    • C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/48—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/29—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

本発明は、非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）および非アルコール性脂肪性肝炎（ＮＡＳＨ）を治療するためのプテロスチルベンアミノ酸含有炭酸塩の新規類縁体に関する。 The present invention relates to novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）は、非アルコール性脂肪性肝疾患としても知られる、肝臓の単純な脂肪浸潤から開始される一連の組織学的変化からなる（１）。非アルコール性脂肪性肝炎（ＮＡＳＨ）は、ＮＡＦＬＤの重度の悪性形態である。それは、線維性肝硬変、肝不全、および肝細胞癌（ＨＣＣ）に進行し得て、末期肝疾患または肝移植Ｃの癌に急速に変化し得る（２、３）。ＮＡＦＬＤは最も一般的な慢性肝疾患であり、世界中の成人人口の４分の１がＮＡＦＬＤを患っている（４）。 Nonalcoholic fatty liver disease (NAFLD), also known as nonalcoholic fatty liver disease, consists of a series of histological changes that begin with simple fatty infiltration of the liver (1). Nonalcoholic steatohepatitis (NASH) is a severe malignant form of NAFLD. It can progress to fibrotic cirrhosis, liver failure, and hepatocellular carcinoma (HCC), and can rapidly transform into end-stage liver disease or cancer requiring liver transplantation (2, 3). NAFLD is the most common chronic liver disease, with one-quarter of the adult population worldwide suffering from NAFLD (4).

現在の推定によると、ＮＡＳＨと診断された成人人口の有病率は、２０２７年までに日本、イギリス、フランス、ドイツ、イタリア、およびスペインにおいて合わせて１，８００万人に達するであろう。食事によるカロリー制限および運動などの生活習慣への介入は、現在のＮＡＳＨの基本的な治療法であるが、薬物治療の緊急性を満たさないことはもちろん、改善および維持が困難であり得る（２）。 According to current estimates, the prevalence of the adult population diagnosed with NASH will reach a combined 18 million in Japan, the UK, France, Germany, Italy, and Spain by 2027. Lifestyle interventions such as dietary calorie restriction and exercise are the current basic treatments for NASH, but they can be difficult to improve and maintain, let alone meet the urgency of drug treatment (2).

ＮＡＳＨ治療薬候補の臨床試験がいくつか開発中であるが（５－７）、現在のところ、米国ＦＤＡから承認されたＮＡＳＨ治療薬は存在しない。臨床試験中の薬剤のうち、オベチコール酸（Ｏｃａｌｉｖａ、主に胆道胆管炎治療薬として知られている）は、現在唯一の第ＩＩＩ相臨床試験薬候補であり、ＮＡＳＨ効力の抑制に良好な結果を得て、その後、米国でのＮＤＡ（新薬申請）を行っている（８、９）。概して、新規で安全かつ有効なＮＡＳＨ／ＮＡＦＬＤ治療薬または予防薬の開発が急務となっている。 Although several clinical trials of potential NASH treatments are under development (5-7), currently no treatments for NASH have been approved by the US FDA. Of the drugs under clinical trial, obeticholic acid (Ocaliva, known primarily for the treatment of biliary cholangitis) is currently the only candidate drug in Phase III clinical trials, which has shown good results in suppressing NASH efficacy and has subsequently submitted a New Drug Application (NDA) in the US (8, 9). Overall, there is an urgent need to develop new, safe and effective drugs for the treatment or prevention of NASH/NAFLD.

プテロスチルベン（トランス－３，５－ジメトキシ－４－ヒドロキシスチルベン）は、主にブルーベリー、ブドウ、および様々な樹木の木に主に見られる天然由来のファイトケミカル化合物である（１０－１２）。プテロスチルベンは、癌、脂質異常症、糖尿病、および認知機能低下などのいくつかの疾患の予防および治療に様々な利点を有することが知られている（１０，１１，１３）。 Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a naturally occurring phytochemical compound found primarily in blueberries, grapes, and various tree species (10-12). Pterostilbene is known to have various benefits in the prevention and treatment of several diseases such as cancer, dyslipidemia, diabetes, and cognitive decline (10, 11, 13).

近年、プテロスチルベンが肥満ラットの肝脂肪症を軽減し、肝脂肪酸プロファイルを修正することが報告されている（１４，１５）。プテロスチルベンを動物、およびヒト実験の両方で使用した結果、低毒性および高い安全性を示した（１６）。したがって、プテロスチルベンがＮＡＦＬＤ／ＮＡＳＨの治療のための臨床薬として開発される可能性は高い。しかしながら、プテロスチルベンは水溶性が０．０１１ｍｇ／ｍＬと低く（ｗｗｗ．ｖｃｃｌａｂ．ｏｒｇ）、臨床研究には不向きである。一部の創薬化学者は、これを水溶性のリン酸塩誘導体に誘導している（１７）。一般にフェノールリン酸塩は安定性が低いため、経口製剤化されることはほとんどない。これまでのところ、プテロスチルベンリン酸塩の経口でのインビボ有効性に関する文献はない。ｉｖの動物実験が報告されているのみである（１８）。その後、Ｃｈａｖａ ｓａｔｙａｎａｒａｙａｎａらは、プテロスチルベンリン酸塩およびシタグリプチン（経口活性なジペプチジルペプチダーゼ－４、（ＤＰＰ－ＩＶ）酵素阻害剤）を、結晶形態（または非晶質形態）のシタグリプチンプテロスチルベンリン酸塩の治療有効量を含む医薬組成物とした（Ｃｈａｖａ ｓａｔｙａｎａｒａｙａｎａ ｅｔ．ａｌ．特許番号：国際公開第２０１４／１４７６４１号）。本化合物は
、シタグリプチンをベースとしている。本特許は、シタグリプションプテロスチルベンリン酸塩に関するもので、調製方法および同様の医薬組成物を含むが、インビボでの有効性の結果は含まない。 Recently, it has been reported that pterostilbene reduces hepatic steatosis and modifies hepatic fatty acid profile in obese rats (14, 15). The results of using pterostilbene in both animal and human experiments showed low toxicity and high safety (16). Therefore, it is highly likely that pterostilbene will be developed as a clinical drug for the treatment of NAFLD/NASH. However, pterostilbene has a low water solubility of 0.011 mg/mL (www.vcclab.org), making it unsuitable for clinical studies. Some medicinal chemists have derived it into a water-soluble phosphate derivative (17). In general, phenol phosphates are rarely formulated orally due to their low stability. So far, there is no literature on the oral in vivo efficacy of pterostilbene phosphate. Only iv animal studies have been reported (18). Subsequently, Chava Satyanarayana et al. formulated pterostilbene phosphate and sitagliptin (an orally active dipeptidyl peptidase-4, (DPP-IV) enzyme inhibitor) into a pharmaceutical composition containing a therapeutically effective amount of sitagliptin pterostilbene phosphate in crystalline (or amorphous) form (Chava Satyanarayana et.al. Patent No.: WO 2014/147641). The compound is based on sitagliptin. The patent relates to sitagliptin pterostilbene phosphate, including preparation methods and similar pharmaceutical compositions, but does not include in vivo efficacy results.

Ａｚｚｏｌｉｎｉ Ｍらは、プテロスチルベンアミノ酸カルバメートの一連の水溶性誘導体を合成し（１９）、その薬物動態および分布プロファイルを試験し、吸収の増加および代謝の減少を見出したが、さらにインビボでの有効性を試験していない。その理由として考えられるのは、カルバメートのエステル結合の体内での分解が非常に遅く、カルバメートの誘導体が生物学的に活性な代謝物（例えば、イリノテカン）に変換されないためと考えられる。さらに、Ｇｏｎｚａｌｅｚ－Ａｌｆｏｎｓｏ ＪＬらは、水溶性に優れた新規の一連の８－アームポリエチレングリコールプテロスチルベン誘導体を合成したが、抗腫瘍活性の試験はＩＶ法のみ行った（２０）。Ｋｕｏらは、扁平上皮癌および肝癌の阻害剤として一連のスチルベノイドを合成した（Ｋｕｏ Ｓｈｅｎｇ－Ｃｈｕ ｅｔ ａｌ．米国特許第９．２６６．８１３号明細書、２０１６）。合成したスチルベノイドのうち、水溶性のプテロスチルベノイドの一部は不安定であり、安定なプテロスチルベノイドの一部は水溶性に乏しい。近年、Ｊｏｓｅ’Ｌらはプテロスチルベンα－グルコシドを酵素により合成した（Ｓｙｔｈｅａｉｚｅｄ）。その水溶性は向上したが、インビボでの有効性についての報告はない（２０）。 Azzolini M et al. synthesized a series of water-soluble derivatives of pterostilbene amino acid carbamates (19), tested their pharmacokinetic and distribution profiles, and found increased absorption and decreased metabolism, but did not further test their efficacy in vivo. This is probably because the ester bond of carbamates is degraded very slowly in the body, and the carbamate derivatives are not converted to biologically active metabolites (e.g., irinotecan). In addition, Gonzalez-Alfonso JL et al. synthesized a novel series of 8-arm polyethylene glycol pterostilbene derivatives with excellent water solubility, but only tested their antitumor activity by IV method (20). Kuo et al. synthesized a series of stilbenoids as inhibitors of squamous cell carcinoma and hepatoma (Kuo Sheng-Chu et al. US Patent No. 9.266.813, 2016). Among the synthesized stilbenoids, some of the water-soluble pterostilbenoids are unstable, and some of the stable pterostilbenoids are poorly water-soluble. Recently, Jose'L et al. synthesized pterostilbene α-glucoside using an enzyme (Sytheaized). Its water solubility was improved, but there have been no reports of its effectiveness in vivo (20).

本発明の目的は、以下の式を有する一連の新規化合物、またはその薬学的に許容される塩を提供することである： The object of the present invention is to provide a series of novel compounds having the following formula, or a pharma- ceutically acceptable salt thereof:

式中、ｎは１～３であり；
ｍは２～６であり；
Ｑ、ＸおよびＹはそれぞれ独立に、Ｏ、Ｓ、またはＮＨであり；
Ｒａ、ＲｂおよびＲｃは、それぞれ独立に、Ｈ、ハロゲン、Ｃ１～Ｃ６直鎖アルキル、Ｃ１～Ｃ６直鎖アルコキシ、Ｃ３～Ｃ６分枝アルキル、Ｃ３～Ｃ６分枝アルコキシまたはＣ１～Ｃ６フルオロアルコキシであり；
ＲｄおよびＲｅは、それぞれ独立に、Ｈ、ハロゲン、Ｃ１～Ｃ６直鎖アルキル、Ｃ１～Ｃ６直鎖アルコキシ、Ｃ３～Ｃ６分枝アルキル、Ｃ３～Ｃ６分枝アルコキシもしくはＣ１～Ｃ６フルオロアルコキシ、またはＲｄとＲｅとが連結して環状構造を形成し、 wherein n is 1 to 3;
m is 2 to 6;
Q, X and Y are each independently O, S, or NH;
Ra, Rb and Rc are each independently H, halogen, C1-C6 straight chain alkyl, C1-C6 straight chain alkoxy, C3-C6 branched alkyl, C3-C6 branched alkoxy or C1-C6 fluoroalkoxy;
Rd and Re each independently represent H, halogen, C1-C6 linear alkyl, C1-C6 linear alkoxy, C3-C6 branched alkyl, C3-C6 branched alkoxy or C1-C6 fluoroalkoxy, or Rd and Re are linked to form a cyclic structure;

となり、式中、ｊは１～３である。 where j is 1 to 3.

本発明の他の目的は、患者における非アルコール性脂肪性肝疾患および非アルコール性脂肪性肝炎を治療するための医薬の製造における、本発明の化合物またはその薬学的に許容される塩の新規な使用を提供することである。 Another object of the present invention is to provide a novel use of a compound of the present invention or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in a patient.

本発明のさらに他の目的は、対象における非アルコール性脂肪性肝疾患または非アルコール性脂肪性肝炎を治療するための医薬組成物であって、本発明の化合物、またはその薬学的に許容される塩の前記治療のための治療有効量を含む、医薬組成物を提供することである。 Yet another object of the present invention is to provide a pharmaceutical composition for treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject, comprising a therapeutically effective amount for said treatment of a compound of the present invention, or a pharma- ceutical acceptable salt thereof.

本発明は、さらに、本発明の化合物またはその薬学的に許容される塩の有効量を、前記治療を必要とする、非アルコール性脂肪性肝疾患または非アルコール性脂肪性肝炎を患う対象に投与することを含む、非アルコール性脂肪性肝疾患または非アルコール性脂肪性肝炎の治療方法を提供するものである。 The present invention further provides a method for treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, comprising administering an effective amount of a compound of the present invention or a pharma- ceutical acceptable salt thereof to a subject suffering from non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in need of said treatment.

本発明はまた、本発明の化合物またはその薬学的に許容される塩の合成に有用な中間体化合物であって、以下の式を有する化合物を提供するものである： The present invention also provides an intermediate compound useful in the synthesis of the compounds of the present invention or pharma- ceutically acceptable salts thereof, the compound having the following formula:

式中、ｍ、Ｒｃ、Ｒｄ、およびＲｅは上記のように定義され、Ｂｏｃはビルディングブロック官能基であり、ただし、Ｒｄは水素ではない。本発明の好ましい実施形態は、明細書の末尾にある添付の請求項に記載された特徴を含む（ただし、これに限定されるものではない）。 wherein m, Rc, Rd, and Re are defined as above, and Boc is a building block functional group, with the proviso that Rd is not hydrogen. Preferred embodiments of the present invention include, but are not limited to, the features recited in the appended claims at the end of the specification.

図１は、５群のマウス：シャム群（非ＭＣＤ食）；ＭＣＤ食群；ＭＣＤ食＋本発明の化合物５ｃ ７５ｍｇ／ｋｇ；ＭＣＤ食＋化合物５ｃ １００ｍｇ／ｋｇ；およびＭＣＤ食＋化合物５ｃ １５０ｍｇ／ｋｇ、の肝臓サンプルを示す写真（倍率：２００倍）であり、前記肝臓をヘマトキシリン・エオジン（Ｈ＆Ｅ）染色し、位相差顕微鏡を用いて撮影した。FIG. 1 is a photograph (magnification: 200x) showing liver samples from five groups of mice: Sham group (non-MCD diet); MCD diet group; MCD diet + 75 mg/kg of compound 5c of the present invention; MCD diet + 100 mg/kg of compound 5c; and MCD diet + 150 mg/kg of compound 5c. The livers were stained with hematoxylin and eosin (H&E) and photographed using a phase contrast microscope. 図２は、２４時間における２５℃での化合物５ｃのＨ２Ｏへの溶解度を示す。FIG. 2 shows the solubility of compound 5c in H 2 O at 25° C. over 24 hours.

発明の詳細な説明
本発明の好ましい実施形態に従って、非アルコール性脂肪性肝疾患および非アルコール性脂肪性肝炎（ＮＡＳＨ）の治療活性を示す一連の水溶性プテロスチルベンアミノ酸含有炭酸塩の新規類縁体を合成した。 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In accordance with preferred embodiments of the present invention, a series of novel water-soluble pterostilbene amino acid-containing carbonate analogs have been synthesized that exhibit therapeutic activity for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

１．化学合成
１－１．原料および機器
出発原料、試薬および溶媒は市販品（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ、Ａｃｒｏｓ、ＴＣ
Ｉ、Ａｌｆａ、Ｃｏｍｂｉ－Ｂｌｏｃｋｓ、Ｍａｔｒｉｘ、およびＦｉｓｃｈｅｒ）から購入し、さらなる精製はせずに受け取った状態で使用した。１Ｈおよび１３Ｃ－ＮＭＲスペクトルは，Ｖａｒｉａｎ ＡＳ５００ ５００ ＮＭＲ－ｓｐｅｃｔｒｏｍｅｔｅｒまたはＡｇｉｌｅｎｔ Ｔｅｃｈｎｏｌｏｇｉｅｓ ＶｎｍｒＪ ５００ ＮＭＲ－ｓｐｅｃｔｒｏｍｅｔｅｒを用いて、表示した溶媒中で測定した。化学シフトは内部標準であるＴＭＳシグナルに対するｐｐｍ（δ単位）で表示されている。フラッシュカラムクロマトグラフィーは、Ｍｅｒｃｋ ｓｉｌｉｃａ ｇｅｌ ６０（０．０６３～０．２００μｍ）を充填したカラムで実施した。化合物または最終化合物の精製は、Ｉｎｅｒｔｓｉｌ ＯＤＳ－３ Ｃ１８（５μｍ、３０ｍｍ×２５０ｍｍ）カラムを用いて、２２０または２５４ｎｍにおいてＵＶ検出（Ｊａｓｃｏ ＵＶ－９７５検出器）を行う逆相高速液体クロマトグラフィー（ＲＰ－ＨＰＬＣ）で行った。移動相はＨ２ＯおよびＣＨ３ＣＮ（溶離液Ａ、７０％ＡＣＮまたは８０％ＡＣＮ、アイソクラティック、流量４２ｍＬ／分；溶離液Ｂ、グラジエント、詳細は実験に記載）から構成された。電子衝撃によるマススペクトル（ＭＳ）は、ＡＰＩ ３２００ ＬＣ／ＭＳ／ＭＳで記録された。溶媒は試薬グレードを使用し、必要に応じて標準的な方法で精製、乾燥させた。反応溶液の濃縮は、ロータリーエバポレーターを使用し、減圧下で行った。 1. Chemical synthesis 1-1. Materials and equipment Starting materials, reagents and solvents were commercially available (Sigma-Aldrich, Acros, TC
I, Alfa, Combi-Blocks, Matrix, and Fischer) and were used as received without further purification. 1 H and 13 C-NMR spectra were measured on a Varian AS500 500 NMR-spectrometer or an Agilent Technologies VnmrJ 500 NMR-spectrometer in the solvents indicated. Chemical shifts are given in ppm (δ units) relative to the TMS signal, which is an internal standard. Flash column chromatography was performed on columns packed with Merck silica gel 60 (0.063-0.200 μm). Purification of compounds or final compounds was performed by reversed-phase high-performance liquid chromatography (RP-HPLC) using an Inertsil ODS-3 C18 (5 μm, 30 mm×250 mm) column with UV detection at 220 or 254 nm (Jasco UV-975 detector). The mobile phase consisted of H 2 O and CH 3 CN (eluent A, 70% or 80% ACN, isocratic, flow rate 42 mL/min; eluent B, gradient, details described in the Experimental section). Electron impact mass spectra (MS) were recorded on an API 3200 LC/MS/MS. Solvents were of reagent grade and, if necessary, were purified and dried by standard methods. Reaction solutions were concentrated under reduced pressure using a rotary evaporator.

１－２．目的化合物５ａ～１０の合成
１－２－１．化合物５ａ～５ｓの合成
スキーム１に従って目的化合物５ａ～５ｓを合成した。各種アミノ酸（１ａ～１ｓ）をＣＨ２Ｃｌ２中、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、およびＮ，Ｎ－ジメチルアミノピリジン（ＤＭＡＰ）の存在下において、または１－［ビス（ジメチルアミノ）メチレン］－１Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジニウム３－オキシドヘキサフルオロホスファート（ＨＡＴＵ）、およびＤＩＰＥＡの存在下において、エタノールアミンと反応させ、対応するヒドロキシルアミド誘導体（化合物２ａ～２ｓ）を得た。その後、１，４－ジオキサン中４Ｍ ＨＣｌ、またはＣＨ２Ｃｌ２中トリフルオロ酢酸（ＴＦＡ）およびトリイソプロピルシラン（ＴＩＰＳ）、で脱保護し、目的化合物５ａ～５ｓを得た。 1-2. Synthesis of target compounds 5a to 10 1-2-1. Synthesis of compounds 5a to 5s Target compounds 5a to 5s were synthesized according to Scheme 1. Various amino acids (1a to 1s) were reacted with ethanolamine in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), diisopropylethylamine (DIPEA), and N,N-dimethylaminopyridine (DMAP) in CH 2 Cl 2, or in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and DIPEA, to obtain the corresponding hydroxylamide derivatives (compounds 2a to 2s). Subsequent deprotection with 4M HCl in 1,4-dioxane, or trifluoroacetic acid (TFA) and triisopropylsilane (TIPS) in CH 2 Cl 2 afforded the target compounds 5a-5s.

スキーム１：化合物５ａ～５ｓの合成 Scheme 1: Synthesis of compounds 5a-5s

試薬および条件：（ａ）ＥＤＣＩ，ＤＩＰＥＡ，ＤＭＡＰ，ＣＨ２Ｃｌ２またはＨＡＴＵ，ＤＩＰＥＡ，ＣＨ２Ｃｌ２；（ｂ）ＮＥｔ３，ＣＨ２Ｃｌ２；（ｃ）ＤＭＡＰ，ＡＣＮ，５０℃；（ｄ）１，４－ジオキサン中４Ｍ ＨＣｌ，またはＴＦＡ，ＴＩＰＳ，ＣＨ
２Ｃｌ２。 Reagents and conditions: (a) EDCI, DIPEA, DMAP, CH 2 Cl 2 or HATU, DIPEA, CH 2 Cl 2 ; (b) NEt 3 , CH 2 Cl 2 ; (c) DMAP, ACN, 50° C.; (d) 4M HCl in 1,4-dioxane, or TFA, TIPS, CH
2Cl2 .

ｔｅｒｔ－ブチル（２－（（２－ヒドロキシエチル）アミノ）－２－オキソエチル）カルバメート（２ａ）
ＣＨ２Ｃｌ２（８０ｍＬ）中のエタノールアミン（３．０３ｇ，４９．６ｍｍｏｌ），Ｂｏｃ－Ｇｌｙ－ＯＨ １ａ（７．２ｇ，４１．３ｍｍｏｌ）およびＤＩＰＥＡ（１６ｇ，１２４ｍｍｏｌ）の撹拌溶液に、ＥＤＣＩ（６１．７ｇ，４６．６ｍｍｏｌ）を添加した。反応混合物を室温で１２時間撹拌した。反応後、溶媒を真空除去し、残渣をカラムクロマトグラフィー（ｎ－ヘキサンからＥＡ／ｎ－ヘキサン＝１／５（Ｖ／Ｖ））で精製し、目的生成物２ａ（３．３ｇ，収率３７％）を白色粉末として得た。1H-NMR (CDCl3, 500
MHz), δ (ppm): 6.98 (s, NH), 5.62 (s, NH), 3.80 (s, 2H), 3.70-3.68 (m, 2H), 3.43-3.40 (m, 2H), 3.25 (s, OH), 1.44 (s, 9H)。 tert-Butyl (2-((2-hydroxyethyl)amino)-2-oxoethyl)carbamate (2a)
To a stirred solution of ethanolamine (3.03 g, 49.6 mmol), Boc-Gly-OH 1a (7.2 g, 41.3 mmol) and DIPEA (16 g, 124 mmol) in CH 2 Cl 2 (80 mL) was added EDCI (61.7 g, 46.6 mmol). The reaction mixture was stirred at room temperature for 12 h. After the reaction, the solvent was removed in vacuum and the residue was purified by column chromatography (n-hexane to EA/n-hexane=1/5 (V/V)) to give the desired product 2a (3.3 g, 37% yield) as a white powder. 1 H-NMR (CDCl 3 , 500
MHz), δ (ppm): 6.98 (s, NH), 5.62 (s, NH), 3.80 (s, 2H), 3.70-3.68 (m, 2H), 3.43-3.40 (m, 2H), 3.25 (s, OH), 1.44 (s, 9H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１－オキソプロパン－２－イル）カルバメート（２ｂ）
２ａと同様の合成手順でＢｏｃ－Ａｌａ－ＯＨ １ｂから２ｂを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1-oxopropan-2-yl)carbamate (2b)
Following a similar synthetic procedure to 2a, 2b was obtained from Boc-Ala-OH 1b.

収率３７％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.90 (s, NH), 5.37 (s, NH), 4.13-4.10 (m, 2H), 3.69-3.68 (m, 2H), 3.44-3.43 (m, 1H), 3.37-3.36 (m, 1H), 1.43 (s, 9H), 1.35 (d, J = 6.5 Hz, 3H)。 Yield 37%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.90 (s, NH), 5.37 (s, NH), 4.13-4.10 (m, 2H), 3.69-3.68 (m, 2H), 3.44-3.43 (m, 1H), 3.37-3.36 (m, 1H), 1.43 (s, 9H), 1.35 (d, J = 6.5 Hz, 3H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（２ｃ）
ＣＨ２Ｃｌ２（４０ｍＬ）中のエタノールアミン（３３５ｍｇ，５．４８１９ｍｍｏｌ），Ｂｏｃ－Ｖａｌ－ＯＨ １ｃ（１１９１ｍｇ，５．５ｍｍｏｌ）およびＤＩＰＥＡ（２３８７ｕＬ，１３．７ｍｍｏｌ）の撹拌溶液に、ＨＡＴＵ（２５０１ｍｇ，６．６ｍｍｏｌ）を添加した。反応混合物を室温で１２時間撹拌した。反応後、溶媒を真空除去し、残渣をカラムクロマトグラフィー（ｎ－ヘキサンからＥＡ／ｎ－ヘキサン＝３／１（Ｖ／Ｖ））で精製し、目的生成物２ｃ（１１１３ｍｇ、収率７８％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.65 (s, NH), 5.15 (s, NH), 3.86 (t, J= 7.5 Hz, 1H), 3.70 (s, 2H), 3.49-3.41 (m, 1H), 3.40-3.36 (m, 1H), 3.07 (s, 1H), 2.11-2.10 (m, 1H) 1.43 (s, 9H), 0.96 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H)。 tert-Butyl (1-((2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2c)
To a stirred solution of ethanolamine (335 mg, 5.4819 mmol), Boc-Val-OH 1c (1191 mg, 5.5 mmol) and DIPEA (2387 uL, 13.7 mmol) in CH 2 Cl 2 (40 mL) was added HATU (2501 mg, 6.6 mmol). The reaction mixture was stirred at room temperature for 12 h. After the reaction, the solvent was removed in vacuum and the residue was purified by column chromatography (n-hexane to EA/n-hexane=3/1 (V/V)) to give the desired product 2c (1113 mg, 78% yield) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.65 (s, NH), 5.15 (s, NH), 3.86 (t, J = 7.5 Hz, 1H), 3.70 (s, 2H), 3.49-3.41 (m, 1H), 3.40-3.36 (m, 1H), 3.07 (s, 1H), 2.11-2.10 (m, 1H) 1.43 (s, 9H), 0.96 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－４－メチル－１－オキソペンタン－２－イル）カルバメート（２ｄ）
２ａと同様の合成手順でＢｏｃ－Ｌｅｕ－ＯＨ １ｄから２ｄを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (2d)
Following a similar synthetic procedure to 2a, 2d was obtained from Boc-Leu-OH 1d.

収率７０％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.05 (s, NH), 5.31 (s, NH), 4.13-4.12 (m, 1H), 3.70-3.67 (m, 2H), 3.47-3.44 (m, 1H), 3.38-3.34 (m, 1H), 1.67-1.60 (m, 2H), 1.52-1.47 (m, 1H), 1.42 (s, 9H), 0.94-0.91 (m, 6H)。 Yield 70%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.05 (s, NH), 5.31 (s, NH), 4.13-4.12 (m, 1H), 3.70-3.67 (m, 2H), 3.47-3.44 (m, 1H), 3.38-3.34 (m, 1H), 1.67-1.60 (m, 2H), 1.52-1.47 (m, 1H), 1.42 (s, 9H), 0.94-0.91 (m, 6H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－３－メチル－１－オキソペンタン－２－イル）カルバメート（２ｅ）
２ａと同様の合成手順でＢｏｃ－Ｉｌｅ－ＯＨ １ｅから２ｅを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate (2e)
Following a similar synthetic procedure to 2a, 2e was obtained from Boc-Ile-OH 1e.

収率６４％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.73 (s, NH), 5.19 (s, NH), 3.90 (t, J = 7.0 Hz, 1H), 3.71-3.69 (m, 2H), 3.49-3.44 (m, 1H), 3.39-3.36 (m, 1H), 2.48-2.46 (m, 1H), 1.86-1.84 (m, 1H), 1.56-1.53 (m, 1H), 1.43 (s, 9H), 0.94-0.89
(m, 6H)。 Yield 64%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.73 (s, NH), 5.19 (s, NH), 3.90 (t, J = 7.0 Hz, 1H), 3.71-3.69 (m, 2H), 3.49-3.44 (m, 1H), 3.39-3.36 (m, 1H), 2.48-2.46 (m, 1H), 1.86-1.84 (m, 1H), 1.56-1.53 (m, 1H), 1.43 (s, 9H), 0.94-0.89
(m, 6H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－４－（メチルチオ）－１－オキソブタン－２－イル）カルバメート（２ｆ）
２ｃと同様の合成手順でＢｏｃ－Ｍｅｔ－ＯＨ １ｆから２ｆを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (2f)
Following a similar synthetic procedure to 2c, 2f was obtained from Boc-Met-OH 1f.

収率３２％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.30 (s, NH), 5.73 (s, NH), 4.14-4.12 (m, 1H), 3.59-3.58 (m, 2H), 3.39-3.24 (m, 2H), 2.49-2.46 (m, 2H), 2.05 (s, 3H), 2.02-1.98 (m, 1H), 1.85-1.82 (m, 1H), 1.38 (s, 9H)。 Yield 32%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.30 (s, NH), 5.73 (s, NH), 4.14-4.12 (m, 1H), 3.59-3.58 (m, 2H), 3.39-3.24 (m, 2H), 2.49-2.46 (m, 2H), 2.05 (s, 3H), 2.02-1.98 (m, 1H), 1.85-1.82 (m, 1H), 1.38 (s, 9H).

ｔｅｒｔ－ブチル（３－（ｔｅｒｔ－ブトキシ）－１－（（２－ヒドロキシエチル）アミノ）－１－オキソプロパン－２－イル）カルバメート（２ｇ）
２ａと同様の合成手順でＢｏｃ－Ｓｅｒ（ｔＢｕ）－ＯＨ １ｇから２ｇを得た。 tert-Butyl (3-(tert-butoxy)-1-((2-hydroxyethyl)amino)-1-oxopropan-2-yl)carbamate (2g)
The compound 2g was obtained from Boc-Ser(tBu)-OH 1g by the same synthetic procedure as for 2a.

収率４１％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.93 (s, NH), 5.42 (s, NH), 4.19-4.17 (m, 1H), 3.76 (s, OH), 3.75-3.69 (m, 2H), 3.42-3.40 (m, 2H), 2.55-2.52 (m, 1H) 1.43 (s, 9H), 1.17 (s, 9H)。 Yield 41%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.93 (s, NH), 5.42 (s, NH), 4.19-4.17 (m, 1H), 3.76 (s, OH), 3.75-3.69 (m, 2H), 3.42-3.40 (m, 2H), 2.55-2.52 (m, 1H) 1.43 (s, 9H), 1.17 (s, 9H).

ｔｅｒｔ－ブチル（３－（ｔｅｒｔ－ブトキシ）－１－（（２－ヒドロキシエチル）アミノ）－１－オキソブタン－２－イル）カルバメート（２ｈ）
２ａと同様の合成手順でＢｏｃ－Ｔｈｒ（ｔＢｕ）－ＯＨ １ｈから２ｈを得た。 tert-Butyl (3-(tert-butoxy)-1-((2-hydroxyethyl)amino)-1-oxobutan-2-yl)carbamate (2h)
Following a similar synthetic procedure to 2a, 2h was obtained from Boc-Thr(tBu)-OH 1h.

収率２４％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.12 (s, NH), 5.62 (s, NH), 4.13-4.09 (m, 2H), 3.72-3.70 (m, 2H), 3.49-3.48 (m, 1H), 3.38-3.37 (m, 1H), 1.45 (s, 9H), 1.24 (s, 9H), 1.06 (d, J = 5.5 Hz, 3H)。 Yield 24%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.12 (s, NH), 5.62 (s, NH), 4.13-4.09 (m, 2H), 3.72-3.70 (m, 2H), 3.49-3.48 (m, 1H), 3.38-3.37 (m, 1H), 1.45 (s, 9H), 1.24 (s, 9H), 1.06 (d, J = 5.5 Hz, 3H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１－オキソ－３－（トリチルチオ）プロパン－２－イル）カルバメート（２ｉ）
２ｃと同様の合成手順でＢｏｃ－Ｃｙｓ（Ｔｒｔ）－ＯＨ １ｉから２ｉを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1-oxo-3-(tritylthio)propan-2-yl)carbamate (2i)
Following a similar synthetic procedure to 2c, 2i was obtained from Boc-Cys(Trt)-OH 1i.

収率７１％。1H-NMR (CDCl3, 500 MHz), δ (ppm): .7.42-7.40 (m, 6H), 7.31-7.27 (m, 6H), 7.26-7.20 (m, 3H), 6.42 (s, NH), 4.88 (s, NH), 3.81-3.80 (m, 1H), 3.64-3.63 (m, 2H), 3.34-3.33 (m, 2H), 2.69-2.66 (m, 1H), 2.57-2.53 (m, 1H), 1.41 (s, 9H)。 Yield 71%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): .7.42-7.40 (m, 6H), 7.31-7.27 (m, 6H), 7.26-7.20 (m, 3H), 6.42 (s, NH), 4.88 (s, NH), 3.81-3.80 (m, 1H), 3.64-3.63 (m, 2H), 3.34-3.33 (m, 2H), 2.69-2.66 (m, 1H), 2.57-2.53 (m, 1H), 1.41 (s, 9H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（２ｊ）
２ｃと同様の合成手順でＢｏｃ－Ｐｈｅ－ＯＨ １ｊから２ｊを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (2j)
Following a similar synthetic procedure to 2c, 2j was obtained from Boc-Phe-OH 1j.

収率８８％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 6.21 (brs, 1H, NH), 5.11 (brs, 1H, NH), 4.29 (d, J= 7.0 Hz, 1H), 3.58-3.57 (m, 2H), 3.32 (s, 2H), 3.10-3.01 (m, 2H), 2.44 (brs, 1H, OH), 1.44 (s, 9H)。 Yield: 88%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 6.21 (brs, 1H, NH), 5.11 (brs, 1H, NH), 4.29 (d, J= 7.0 Hz, 1H), 3.58-3.57 (m, 2H), 3.32 (s, 2H), 3.10-3.01 (m, 2H), 2.44 (brs, 1H, OH), 1.44 (s, 9H).

ｔｅｒｔ－ブチル（３－（４－（ｔｅｒｔ－ブトキシ）フェニル）－１－（（２－ヒドロキシエチル）アミノ）－１－オキソプロパン－２－イル）カルバメート（２ｋ）
２ｃと同様の合成手順でＢｏｃ－Ｔｙｒ（ｔＢｕ）－ＯＨ １ｋから２ｋを得た。 tert-Butyl (3-(4-(tert-butoxy)phenyl)-1-((2-hydroxyethyl)amino)-1-oxopropan-2-yl)carbamate (2k)
The same synthetic procedure as for 2c was used to obtain 2k from Boc-Tyr(tBu)-OH 1k.

収率３４％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.09 (d, J= 8.5 Hz, 2H), 6.91 (d, J= 8.5 Hz, 2H), 6.39 (s, NH), 5.22 (s, NH), 4.27-4.26 (m, 1H), 3.59-3.56 (m, 2H), 3.31-3.30 (m, 2H), 2.99-2.97 (m, 2H), 1.40 (s, 9H), 1.32 (s, 9H)。 Yield 34%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.09 (d, J= 8.5 Hz, 2H), 6.91 (d, J= 8.5 Hz, 2H), 6.39 (s, NH), 5.22 (s, NH), 4.27-4.26 (m, 1H), 3.59-3.56 (m, 2H), 3.31-3.30 (m, 2H), 2.99-2.97 (m, 2H), 1.40 (s, 9H), 1.32 (s, 9H).

ｔｅｒｔ－ブチル ３－（２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－（
（２－ヒドロキシエチル）アミノ）－３－オキソプロピル）－１Ｈ－インドール－１－カルボキシラート（２ｌ）
２ａと同様の合成手順でＢｏｃ－Ｔｒｐ（Ｂｏｃ）－ＯＨ １ｌから２ｌを得た。 tert-Butyl 3-(2-((tert-butoxycarbonyl)amino)-3-(
(2-hydroxyethyl)amino)-3-oxopropyl)-1H-indole-1-carboxylate (2l)
The same synthetic procedure as for 2a was used to obtain 2l from Boc-Trp(Boc)-OH 1l.

収率３５％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 8.13-8.11 (m, 1H), 7.60 (d, J =
7.5 Hz, 1H), 7.47 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.28-7.25 (m, 1H), 6.20 (s, NH), 5.18 (s, NH), 4.39-4.38 (m, 1H), 3.60-3.52 (m, 2H), 3.31-3.28 (m, 2H), 3.21-3.14 (m, 2H), 1.67 (s, 9H), 1.43 (s, 9H)。 Yield: 35%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 8.13-8.11 (m, 1H), 7.60 (d, J =
7.5 Hz, 1H), 7.47 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.28-7.25 (m, 1H), 6.20 (s, NH), 5.18 (s, NH), 4.39-4.38 (m, 1H), 3.60-3.52 (m, 2H), 3.31-3.28 (m, 2H), 3.21-3.14 (m, 2H), 1.67 (s, 9H), 1.43 (s, 9H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１－オキソ－３－（１－トリチル－１Ｈ－イミダゾール－２－イル）プロパン－２－イル）カルバメート（２ｍ）
２ｃと同様の合成手順でＢｏｃ－Ｈｉｓ（Ｔｒｔ）－ＯＨ １ｍから２ｍを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-2-yl)propan-2-yl)carbamate (2m)
Following a similar synthetic procedure to 2c, 2m was obtained from Boc-His(Trt)-OH 1m.

収率６７％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.37 (s, 1H), 7.34-7.33 (m, 9H), 7.11-7.10 (m, 6H), 6.34 (s, 1H), 6.57 (s, NH), 5.79 (s, NH), 4.33 (s, 1H), 3.73-3.60 (m, 2H), 3.51 (brs, 1H), 3.21 (brs, 1H), 3.08-3.02 (m, 2H), 1.43 (s, 9H)
。 Yield: 67%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.37 (s, 1H), 7.34-7.33 (m, 9H), 7.11-7.10 (m, 6H), 6.34 (s, 1H), 6.57 (s, NH), 5.79 (s, NH), 4.33 (s, 1H), 3.73-3.60 (m, 2H), 3.51 (brs, 1H), 3.21 (brs, 1H), 3.08-3.02 (m, 2H ), 1.43 (s, 9H)
.

ジ－ｔｅｒｔ－ブチル（６－（（２－ヒドロキシエチル）アミノ）－６－オキソヘキサン－１，５－ジイル）ジカルバメート（２ｎ）
２ｃと同様の合成手順でＢｏｃ－Ｌｙｓ（Ｂｏｃ）－ＯＨ １ｎから２ｎを得た。 Di-tert-butyl(6-((2-hydroxyethyl)amino)-6-oxohexane-1,5-diyl)dicarbamate (2n)
A similar synthetic procedure to 2c was used to obtain 2n from Boc-Lys(Boc)-OH 1n.

収率７０％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.88 (s, NH), 5.43 (s, NH), 4.78 (s, NH), 4.07-4.04 (m, 1H), 3.70-3.68 (m, 2H), 3.41-3.40 (m, 2H), 3.10-3.09 (m, 2H), 1.85-1.79 (m, 1H), 1.66-1.62 (m, 1H), 1.49-1.46 (m, 2H), 1.42 (s, 18H), 1.39-1.37 (m, 2H)。 Yield 70%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.88 (s, NH), 5.43 (s, NH), 4.78 (s, NH), 4.07-4.04 (m, 1H), 3.70-3.68 (m, 2H), 3.41-3.40 (m, 2H), 3.10-3.09 (m, 2H), 1.85-1.79 (m, 1H), 1.66-1.62 (m, 1H), 1.49-1.46 (m, 2H), 1.42 (s, 18H), 1.39-1.37 (m, 2H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１－オキソ－５－（３－（（２，２，４，６，７－ペンタメチル－２，３－ジヒドロベンゾフラン－５－イル）スルホニル）グアニジノ）ペンタン－２－イル）カルバメート（２ｏ）
２ａと同様の合成手順でＢｏｃ－Ａｒｇ（Ｐｂｆ）－ＯＨ １ｏから２ｏを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1-oxo-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)pentan-2-yl)carbamate (2o)
Following a similar synthetic procedure to 2a, 2o was obtained from Boc-Arg(Pbf)-OH 1o.

収率５０％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.42 (s, NH), 6.37 (s, NH), 5.81 (s, NH), 4.23-4.18 (m, 1H), 3.72-3.71 (m, 2H), 3.42-3.41 (m, 2H), 3.31-3.26 (m, 2H), 2.92 (s, 3H), 2.57 (s, 3H), 2.50 (s, 3H), 2.09 (s, 3H), 1.90-1.56 (m, 4H), 1.46 (s, 6H), 1.42 (s, 9H)。 Yield 50%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.42 (s, NH), 6.37 (s, NH), 5.81 (s, NH), 4.23-4.18 (m, 1H), 3.72-3.71 (m, 2H), 3.42-3.41 (m, 2H), 3.31-3.26 (m, 2H), 2.92 (s, 3H), 2.57 (s, 3H), 2.50 (s, 3H), 2.09 (s, 3H), 1.90-1.56 (m, 4H), 1.46 (s, 6H), 1.42 (s, 9H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１，４－ジオキソ－４－（トリチルアミノ）ブタン－２－イル）カルバメート（２ｐ）
２ａと同様の合成手順でＢｏｃ－Ａｓｎ（Ｔｒｔ）－ＯＨ １ｐから２ｐを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1,4-dioxo-4-(tritylamino)butan-2-yl)carbamate (2p)
A similar synthetic procedure to that for 2a was used to obtain 2p from Boc-Asn(Trt)-OH 1p.

収率３７％1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.30-7.23 (m, 9H), 7.19-7.17 (m, 6H), 7.11 (s, NH), 6.91 (s, NH), 6.06 (s, NH), 4.41 (m, 1H), 3.57-3.55 (m, 2H), 3.31-3.29 (m, 2H), 3.06-3.03 (m, 1H), 2.62-2.58 (m, 1H), 1.93 (s, 1H), 1.42 (s, 9H)。 Yield 37%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.30-7.23 (m, 9H), 7.19-7.17 (m, 6H), 7.11 (s, NH), 6.91 (s, NH), 6.06 (s, NH), 4.41 (m, 1H), 3.57-3.55 (m, 2H), 3.31-3.29 (m, 2H), 3.06-3.03 (m, 1H), 2.62-2.58 (m, 1H), 1.93 (s, 1H), 1.42 (s, 9H).

ｔｅｒｔ－ブチル（１－（（２－ヒドロキシエチル）アミノ）－１，５－ジオキソ－５－（トリチルアミノ）ペンタン－２－イル）カルバメート（２ｑ）
２ｃと同様の合成手順でＢｏｃ－Ｇｌｎ（Ｔｒｔ）－ＯＨ １ｑから２ｑを得た。 tert-Butyl (1-((2-hydroxyethyl)amino)-1,5-dioxo-5-(tritylamino)pentan-2-yl)carbamate (2q)
The same synthetic procedure as for 2c was used to obtain 2q from Boc-Gln(Trt)-OH 1q.

収率５１％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.30-7.23 (m, 15H), 6.83 (s, NH), 5.67 (s, NH), 4.11-3.98 (m, 1H), 3.54-3.53 (m, 2H), 3.32-3.22 (m, 2H), 2.48-2.46 (m, 1H), 2.37-2.34 (m, 1H), 2.04-1.98 (m, 1H), 1.85-1.84 (m, 1H), 1.41 (s, 9H)。 Yield: 51%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.30-7.23 (m, 15H), 6.83 (s, NH), 5.67 (s, NH), 4.11-3.98 (m, 1H), 3.54 -3.53 (m, 2H), 3.32-3.22 (m, 2H), 2.48-2.46 (m, 1H), 2.37-2.34 (m, 1H), 2.04-1.98 (m, 1H), 1.85-1.84 (m, 1H), 1.41 (s, 9H).

ｔｅｒｔ－ブチル ３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－４－（（２－ヒドロキシエチル）アミノ）－４－オキソブタノエート（２ｒ）
２ａと同様の合成手順でＢｏｃ－Ａｓｐ（ｔＢｕ）－ＯＨ １ｒから２ｒを得た。 tert-Butyl 3-((tert-butoxycarbonyl)amino)-4-((2-hydroxyethyl)amino)-4-oxobutanoate (2r)
Following a similar synthetic procedure to 2a, 2r was obtained from Boc-Asp(tBu)-OH 1r.

収率３７％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.93 (s, NH), 5.63 (s, NH), 4.43-4.40 (m, 1H), 3.70-3.68 (m, 2H), 3.44-3.37 (m, 2H), 2.87-2.83 (m, 1H), 2.66-2.64 (m, 1H), 1.44 (s, 9H), 1.43 (s, 9H)。 Yield 37%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.93 (s, NH), 5.63 (s, NH), 4.43-4.40 (m, 1H), 3.70-3.68 (m, 2H), 3.44-3.37 (m, 2H), 2.87-2.83 (m, 1H), 2.66-2.64 (m, 1H), 1.44 (s, 9H), 1.43 (s, 9H).

ｔｅｒｔ－ブチル ４－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－５－（（２－ヒドロキシエチル）アミノ）－５－オキソペンタノエート（２ｓ）
２ａと同様の合成手順でＢｏｃ－Ｇｌｕ（ｔＢｕ）－ＯＨ １ｓから２ｓを得た。 tert-Butyl 4-((tert-butoxycarbonyl)amino)-5-((2-hydroxyethyl)amino)-5-oxopentanoate (2s)
The same synthetic procedure as for 2a was used to obtain 2s from Boc-Glu(tBu)-OH 1s.

収率３７％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 6.96 (s, NH), 5.52 (s, NH), 4.13-4.10 (m, 1H), 3.69-3.68 (m, 2H), 3.41-3.40 (m, 2H), 2.39-2.30 (m, 2H), 2.05-2.03 (m, 1H), 1.91-1.88 (m, 1H), 1.43 (s, 9H), 1.42 (s, 9H)。 Yield 37%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 6.96 (s, NH), 5.52 (s, NH), 4.13-4.10 (m, 1H), 3.69-3.68 (m, 2H), 3.41-3.40 (m, 2H), 2.39-2.30 (m, 2H), 2.05-2.03 (m, 1H), 1.91-1.88 (m, 1H), 1.43 (s, 9H), 1.42 (s, 9H).

ｔｅｒｔ－ブチル（Ｅ）－（２－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－２－オキソエチル）カルバメート（４ａ）の合成
脱水ＣＨ２Ｃｌ２（１５ｍｌ）中の化合物２ａ（２．０２ｇ、９．３ｍｍｏｌ）の撹拌溶液にトリエチルアミン（３．２２ｍＬ、２３．１ｍｍｏｌ）を加え、４－ニトロフェニルクロロホルメート溶液（１．９６ｇ、９．７ｍｍｏｌ、１０ｍＬ ＣＨ２Ｃｌ２中）を０℃で滴下して添加した。反応混合物を０℃で１５分間撹拌した後、室温に温めた。混合物を室温でさらに４時間撹拌した。反応終了後（ＴＬＣで確認）、溶媒を蒸発させて除去した。粗中間体をＡＣＮ（２０ｍｌ）中のプテロシルベベ（２．５０ｇ，９．８ｍｍｏｌ）およびＤＭＡＰ（２．２７ｇ，１８．６ｍｍｏｌ）と混合した。得られた混合物を５０℃まで１時間加熱した。反応後、溶媒を真空下で除去した。残渣をＥＡに取り込み、飽和クエン酸水溶液で洗浄した。有機層を回収し、Ｎａ２ＳＯ４上で乾燥させ、蒸発させた。残渣をカラムクロマトグラフィー（シリカゲル、０～２５％ＥｔＯＡｃ／ｎ－ヘキサン）で精製して粗生成物を得て、これを分取ＨＰＬＣ（７０％ＡＣＮ，３０％Ｈ２Ｏ）でさらに精製して目的化合物４ａ（２．２２ｇ，収率４８％）を白い粉末として得た。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.5 Hz, 2H), 6.51 (brs, NH), 6.41 (t, J = 2.5 Hz, 1H), 5.10 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 3.84-3.79 (m, 8H), 3.67 (q, J= 5.5 Hz, 2H), 1.46 (s, 9H). Mass found [M - Boc + H]+ = 402.2; [M + H]+ = 502.2, [M + Na]+ = 524.2, [2M + H]+ = 902.4。 Synthesis of tert-butyl (E)-(2-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-2-oxoethyl)carbamate (4a) To a stirred solution of compound 2a (2.02 g, 9.3 mmol) in dry CH 2 Cl 2 (15 ml) was added triethylamine (3.22 mL, 23.1 mmol) and a solution of 4-nitrophenyl chloroformate (1.96 g, 9.7 mmol, 10 mL in CH 2 Cl 2 ) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 4 h. After completion of the reaction (checked by TLC), the solvent was removed by evaporation. The crude intermediate was mixed with pterosylvebe (2.50 g, 9.8 mmol) and DMAP (2.27 g, 18.6 mmol) in ACN (20 ml). The resulting mixture was heated to 50° C. for 1 h. After the reaction, the solvent was removed under vacuum. The residue was taken up in EA and washed with saturated aqueous citric acid. The organic layer was collected, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography (silica gel, 0-25% EtOAc/n-hexane) to give the crude product, which was further purified by preparative HPLC (70% ACN, 30% H 2 O) to give the target compound 4a (2.22 g, 48% yield) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.5 Hz, 2H), 6.51 (brs, NH), 6.41 (t, J = 2.5 Hz, 1H), 5.10 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 3.84-3.79 (m, 8H), 3.67 (q, J= 5.5 Hz, 2H), 1.46 (s, 9H). Mass found [M-Boc+H] + = 402.2; [M+H] + = 502.2, [M+Na] + = 524.2, [2M+H] + = 902.4.

中間体４ｂ～４ｓを４ａと同様の合成手順で合成した。 Intermediates 4b to 4s were synthesized using the same synthetic procedure as 4a.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソプロパン－２－イル）カルバメート（４ｂ）
４ａと同様の合成手順で２ｂから４ｂを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxopropan-2-yl)carbamate (4b)
4b was obtained from 2b via a similar synthetic procedure to 4a.

収率５６％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.67 (s, 2H), 6.58 (s, 1H), 6.41 (s, 1H), 4.94 (s, 1H), 4.34 (t, J = 5.0 Hz, 2H), 4.17 (s, 1H), 3.84 (s, 6H), 3.65-3.64 (m, 1H), 1.46 (s, 9H), 1.38 (d, J = 7.5 Hz, 3H). Mass found [M - Boc + H]+ = 416.2; [M + H]+ = 516.3, [M + Na]+= 538.3。 Yield: 56%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.67 (s, 2H), 6.58 (s, 1H), 6.41 (s, 1H), 4.94 (s, 1H), 4.34 (t, J = 5.0 Hz, 2H), 4.17 (s, 1H), 3.84 (s, 6H), 3.65-3.64 (m, 1H), 1.46 (s, 9H), 1.38 (d, J = 7.5 Hz, 3H). Mass found [M-Boc+H] + = 416.2; [M+H] + = 516.3, [M+Na] + = 538.3.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（４ｃ）
４ａと同様の合成手順で２ｃから４ｃを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (4c)
4c was obtained from 2c via a similar synthetic procedure to 4a.

収率７８％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.0 Hz, 1H), 6.99 (d, J= 16.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41-6.60 (m, 2H), 5.03 (s, 1H), 4.34 (t, J = 5.0 Hz, 2H), 3.93-3.83 (m, 1H), 3.70 (s, 6H), 3.68-3.63 (m, 2H), 2.17-2.16 (m, 1H) 1.45 (s, 9H), 0.98 (d, J = 6.5 Hz, 3H), 0.93 (d, J= 6.5 Hz, 3H). Mass found [M - Boc + H]+ = 444.1; [M + Na]+ = 566.1。 Yield: 78%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.0 Hz, 1H), 6.99 (d, J= 16.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41-6.60 (m, 2H), 5.03 (s, 1H), 4.34 (t, J = 5.0 Hz, 2H), 3.93-3.83 (m, 1H), 3.70 (s, 6H), 3.68-3.63 (m, 2H), 2.17-2.16 (m, 1H) 1.45 (s, 9H), 0.98 (d, J = 6.5 Hz, 3H), 0.93 (d, J= 6.5 Hz, 3H). Mass found [M - Boc + H] + = 444.1; [M + Na] + = 566.1.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－４－メチル－１－オキソペンタン－２－イル）カルバメート（４ｄ）の合成
４ａと同様の合成手順で２ｄから４ｄを得た。 Synthesis of tert-butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (4d) 4d was obtained from 2d by the same synthetic procedure as for 4a.

収率３２％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.98 (d, J= 16.5 Hz, 1H), 6.67 (d, J= 2.0 Hz, 2H), 6.55 (s, NH), 6.41 (s, 1H), 4.84 (s, NH), 4.33 (t, J = 5.0 Hz, 2H), 4.11 (s, 1H), 3.84 (s, 6H), 3.64 (dd, J= 5.0, 10.5 Hz, 2H), 1.73-1.66 (m, 2H), 1.51-1.47 (m, 1H), 1.45 (s, 9H), 0.96-0.94 (m, 6H). Mass found [M - Boc + H]+= 457.3; [M - Boc + Na]+ = 479.2; [M + Na]+= 579.3; [2M + Na]+ = 1135.5。 Yield: 32%. 1H -NMR ( CDCl3 , 500MHz), δ (ppm): 7.51 (d, J= 8.5Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.06 (d, J= 16.5Hz, 1H), 6.98 (d, J= 16.5Hz, 1H), 6.67 (d, J= 2.0Hz, 2H), 6.55 (s, NH), 6.41 (s, 1H), 4.84 (s, NH), 4.33 (t, J = 5.0Hz, 2H), 4.11 (s, 1H), 3.84 (s, 6H), 3.64 (dd, J= 5.0, 10.5Hz, 2H), 1.73-1.66 (m, 2H), 1.51-1.47 (m, 1H), 1.45 (s, 9H), 0.96-0.94 (m, 6H). Mass found [M - Boc + H] + = 457.3; [M - Boc + Na] + = 479.2; [M + Na] + = 579.3; [2M + Na] + = 1135.5.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－３－メチル－１－オキソペンタン－２－イル）カルバメート（４ｅ）
４ａと同様の合成手順で２ｅから４ｅを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxopentan-2-yl)carbamate (4e)
4e was obtained from 2e via a similar synthetic procedure to 4a.

収率２７％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.51 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 16.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 2H), 6.41-6.40 (m, 2H), 5.02 (s, NH), 4.34 (t, J = 5.0 Hz, 2H), 3.98-3.94 (m, 1H), 3.83 (s, 6H), 3.71-3.61 (m, 2H), 1.92-1.91 (m, 1H), 1.57-1.51
(m, 1H), 1.45 (s, 9H), 1.18-1.09 (m, 1H), 0.95-0.88 (m, 6H). Mass found [M - Boc + H]+ = 457.3; [M + Na]+ = 579.3; [2M + H]+ = 1135.5。 Yield 27%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.51 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 16.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 2H), 6.41-6.40 (m, 2H), 5.02 (s, NH), 4.34 (t, J = 5.0 Hz, 2H), 3.98-3.94 (m, 1H), 3.83 (s, 6H), 3.71-3.61 (m, 2H), 1.92-1.91 (m, 1H), 1.57-1.51
(m, 1H), 1.45 (s, 9H), 1.18-1.09 (m, 1H), 0.95-0.88 (m, 6H). Mass found [M-Boc+H] + = 457.3; [M+Na] + = 579.3; [2M+H] + = 1135.5.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－４－（メチルチオ）－１－オキソブタン－２－イル）カルバメート（４ｆ）
４ａと同様の合成手順で２ｆから４ｆを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (4f)
4f was obtained from 2f via a similar synthetic procedure to 4a.

収率４９％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.52 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.64 (s, NH), 6.41 (t, J = 2.0 Hz, 1H), 5.16 (s, 1H), 4.34 (t, J
= 5.0 Hz, 2H), 4.32-4.28 (m, 1H), 3.84 (s, 6H), 3.69-3.61 (m, 2H), 2.63-2.52 (m, 2H), 2.16-2.08 (m, 4H), 1.98-1.92 (m, 1H), 1.45 (s, 9H). Mass found [M - Boc +
H]+ = 476.2; [M + H]+ = 576.3; [M + Na]+= 598.3。 Yield: 49%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.52 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.64 (s, NH), 6.41 (t, J = 2.0 Hz, 1H), 5.16 (s, 1H), 4.34 (t, J
= 5.0 Hz, 2H), 4.32-4.28 (m, 1H), 3.84 (s, 6H), 3.69-3.61 (m, 2H), 2.63-2.52 (m, 2H), 2.16-2.08 (m, 4H), 1.98-1.92 (m, 1H), 1.45 (s, 9H). Mass found [M - Boc +
[H] + = 476.2; [M + H] + = 576.3; [M + Na] + = 598.3.

ｔｅｒｔ－ブチル（Ｅ）－（３－（ｔｅｒｔ－ブトキシ）－１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソプロパン－２－イル）カルバメート（４ｇ）
４ａと同様の合成手順で２ｇから４ｇを得た。 tert-Butyl (E)-(3-(tert-butoxy)-1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxopropan-2-yl)carbamate (4g)
4g was obtained from 2g by the same synthetic procedure as for 4a.

収率４６％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.16 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 5.44 (s, NH), 4.33 (t, J = 5.0 Hz, 2H),
4.19 (s, 1H), 3.84 (s, 6H), 3.80 (s, 1H), 3.68-3.64 (m, 2H), 3.41-3.39 (m, 1H),
1.46 (s, 9H), 1.20 (s, 9H). Mass found [M - Boc - tBu + H]+= 432.3; [M + H]+ = 588.5; [M + Na]+ = 610.4; [2M + H]+= 1174.8; [2M + Na]+ = 1196.9。 Yield: 46%. 1H -NMR ( CDCl3 , 500 MHz), δ (ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.16 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 5.44 (s, NH), 4.33 (t, J = 5.0 Hz, 2H),
4.19 (s, 1H), 3.84 (s, 6H), 3.80 (s, 1H), 3.68-3.64 (m, 2H), 3.41-3.39 (m, 1H),
1.46 (s, 9H), 1.20 (s, 9H). Mass found [M - Boc - tBu + H] + = 432.3; [M + H] + = 588.5; [M + Na] + = 610.4; [2M + H] + = 1174.8; [2M + Na] + = 1196.9.

ｔｅｒｔ－ブチル（Ｅ）－（３－（ｔｅｒｔ－ブトキシ）－１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソブタン－２－イル）カルバメート（４ｈ）
４ａと同様の合成手順で２ｈから４ｈを得た。 tert-Butyl (E)-(3-(tert-butoxy)-1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxobutan-2-yl)carbamate (4h)
4h was obtained from 2h via a similar synthetic procedure to 4a.

収率４８％。1H-NMR (CDCl3, 500 MHz), δ (ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.34 (s, NH), 7.16 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 16.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 2H), 6.41 (t, J = 2.5 Hz, 1H), 5.64 (d, J= 5.0 Hz, NH), 4.37-4.31 (m, 2H), 4.15-4.13 (m, 2H), 3.84 (s, 6H), 3.69-3.65 (m, 2H), 1.46
(s, 9H), 1.28 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). Mass found [M - Boc - tBu + H]+ = 446.2; [M + H]+= 602.5; [M + Na]+ = 624.4; [2M + H]+ = 1202.9; [2M + Na]+= 1224.9。 Yield: 48%. 1H -NMR ( CDCl3 , 500MHz), δ (ppm): 7.51 (d, J = 8.0Hz, 2H), 7.34 (s, NH), 7.16 (d, J = 8.5Hz, 2H), 7.06 (d, J = 16.5Hz, 1H), 6.99 (d, J = 16.5Hz, 1H), 6.66 (d, J = 2.5Hz, 2H), 6.41 (t, J = 2.5Hz, 1H), 5.64 (d, J = 5.0Hz, NH), 4.37-4.31 (m, 2H), 4.15-4.13 (m, 2H), 3.84 (s, 6H), 3.69-3.65 (m, 2H), 1.46
(s, 9H), 1.28 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H). Mass found [M - Boc - tBu + H] + = 446.2; [M + H] + = 602.5; [M + Na] + = 624.4; [2M + H] + = 1202.9; [2M + Na] + = 1224.9.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソ－３－（トリチルチオ）プロパン－２－イル）カルバメート（４ｉ）
４ａと同様の合成手順で２ｉから４ｉを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-(tritylthio)propan-2-yl)carbamate (4i)
4i was obtained from 2i via a similar synthetic procedure to 4a.

収率２７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.49 (d, J= 8.5 Hz, 2H), 7.44-7.42 (m, 6H), 7.31-7.28 (m, 6H), 7.24-7.21 (m, 3H), 7.14 (d, J = 8.5 Hz, 2H), 7.06
(d, J = 16.5 Hz, 1H), 6.99 (d, J= 16.0 Hz, 1H), 6.66 (d, J= 2.5 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 6.40 (s, 1H), 4.79 (s, 1H), 4.28 (t, J = 5.0 Hz, 2H), 3.84 (s, 6H), 3.57-3.56 (m, 2H), 2.80-2.77 (m, 1H), 2.58-2.56 (m, 1H), 1.42 (s, 9H), Mass found [M + H]+= 789.3; [M + Na]+ = 811.3。 Yield: 27%. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 7.49 (d, J= 8.5 Hz, 2H), 7.44-7.42 (m, 6H), 7.31-7.28 (m, 6H), 7.24-7.21 (m, 3H), 7.14 (d, J = 8.5 Hz, 2H), 7.06
(d, J = 16.5 Hz, 1H), 6.99 (d, J= 16.0 Hz, 1H), 6.66 (d, J= 2.5 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 6.40 (s, 1H), 4.79 (s, 1H), 4.28 (t, J = 5.0 Hz, 2H), 3.84 (s, 6H), 3.57-3.56 (m, 2H), 2.80-2.77 (m, 1H), 2.58-2.56 (m, 1H), 1.42 (s, 9H), Mass found [M + H] + = 789.3; [M + Na] + = 811.3.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（４ｊ）
４ａと同様の合成手順で２ｊから４ｊを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (4j)
4j was obtained from 2j via a similar synthetic procedure to 4a.

収率４６％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.33-7.30 (m, 2H), 7.24-7.21 (m, 3H), 7.17 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 16.5 Hz, 1H), 7.00 (d, J = 16.5 Hz, 1H), 6.67 (s, 2H), 6.41 (s, 1H), 6.13 (brs, NH), 5.03 (brs, NH), 4.34 (s, 1H) , 4.24-4.23 (m, 1H), 4.17 (s, 1H), 3.84 (s, 6H), 3.56 (s
, 2H), 3.11-3.02 (m, 2H), 1.42 (s, 9H). Mass found [M - Boc + H]+= 492.2; [M + H]+ = 592.4; [M + Na]+ = 614.3。 Yield: 46%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.52 (d, J= 9.0Hz, 2H), 7.33-7.30 (m, 2H), 7.24-7.21 (m, 3H), 7.17 (d, J = 9.0Hz, 2H), 7.07 (d, J = 16.5Hz, 1H), 7.00 (d, J = 16.5Hz, 1H), 6.67 (s, 2H), 6.41 (s, 1H), 6.13 (brs, NH), 5.03 (brs, NH), 4.34 (s, 1H), 4.24-4.23 (m, 1H), 4.17 (s, 1H), 3.84 (s, 6H), 3.56 (s
, 2H), 3.11-3.02 (m, 2H), 1.42 (s, 9H). Mass found [M - Boc + H] + = 492.2; [M + H] + = 592.4; [M + Na] + = 614.3.

ｔｅｒｔ－ブチル（Ｅ）－（３－（４－（ｔｅｒｔ－ブトキシ）フェニル）－１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソプロパン－２－イル）カルバメート（４ｋ）
４ａと同様の合成手順で２ｋから４ｋを得た。 tert-Butyl (E)-(3-(4-(tert-butoxy)phenyl)-1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxopropan-2-yl)carbamate (4k)
4k was obtained from 2k via a similar synthetic procedure to 4a.

収率３９％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.10 (d, J= 7.5 Hz, 2H),7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.93 (d, J= 8.5 Hz, 2H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (s, 1H), 6.18 (t, J = 6.0 Hz, NH), 5.01 (brs, NH), 4.31-4.24 (m, 2H), 4.23-4.19 (m, 1H), 3.84 (s, 6H), 3.60-3.52 (m, 2H), 3.07-2.99 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H). Mass found [M - Boc - tBu + H]+ = 508.2; [M - Boc + H]+= 564.3; [M + H]+ = 664.4, [M + Na]+ = 686.4; [M + K]+= 702.4。 Yield: 39%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.51 (d, J= 8.0Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.10 (d, J= 7.5Hz, 2H),7.06 (d, J= 16.5Hz, 1H), 6.99 (d, J= 16.5Hz, 1H), 6.93 (d, J= 8.5Hz, 2H), 6.66 (d, J= 2.0Hz, 2H), 6.41 (s, 1H), 6.18 (t, J = 6.0Hz, NH), 5.01 (brs, NH), 4.31-4.24 (m, 2H), 4.23-4.19 (m, 1H), 3.84 (s, 6H), 3.60-3.52 (m, 2H), 3.07-2.99 (m, 2H), 1.45 (s, 9H), 1.32 (s, 9H). Mass found [M - Boc - tBu + H] + = 508.2; [M - Boc + H] + = 564.3; [M + H] + = 664.4, [M + Na] + = 686.4; [M + K] + = 702.4.

ｔｅｒｔ－ブチル（Ｅ）－３－（２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－３－オキソプロピル）－１Ｈ－インドール－１－カルボキシラート（４ｌ）
４ａと同様の合成手順で２ｌから４ｌを得た。 tert-Butyl (E)-3-(2-((tert-butoxycarbonyl)amino)-3-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-oxopropyl)-1H-indole-1-carboxylate (4l)
4l was obtained from 2l via a similar synthetic procedure to 4a.

収率３０％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 8.14-8.12 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.51-7.47 (m, 3H), 7.32 (t, J = 8.5 Hz, 1H), 7.26-7.24 (m, 2H), 7.14 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.5 Hz, 1H), 6.30 (s, NH), 5.18 (s, NH), 4.22-4.18 (m, 1H), 4.18-4.10 (m, 1H), 3.83 (s, 6H), 3.52-3.51 (m, 2H), 3.22-3.17 (m, 2H), 1.65 (s, 9H) 1.42 (s, 9H). Mass found [M - 2Boc + H]+ = 530.2; [M - Boc + H]+ = 630.2; [M + H]+ = 730.2; [2M + H]+= 1459.5。 Yield: 30%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 8.14-8.12 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.51-7.47 (m, 3H), 7.32 (t, J = 8.5 Hz, 1H), 7.26-7.24 (m, 2H), 7.14 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.5 Hz, 1H), 6.30 (s, NH), 5.18 (s, NH), 4.22-4.18 (m, 1H), 4.18-4.10 (m, 1H), 3.83 (s, 6H), 3.52-3.51 (m, 2H), 3.22-3.17 (m, 2H), 1.65 (s, 9H) 1.42 (s, 9H). Mass found [M - 2Boc + H] + = 530.2; [M - Boc + H] + = 630.2; [M + H] + = 730.2; [2M + H] + = 1459.5.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソ－３－（１－トリチル－１Ｈ－イミダゾール－２－イル）プロパン－２－イル）カルバメート（４ｍ）
４ａと同様の合成手順で２ｍから４ｍを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-2-yl)propan-2-yl)carbamate (4m)
4m was obtained from 2m via a similar synthetic procedure to 4a.

収率６２％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 8.18 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.43-7.38 (m, 9H), 7.15 (d, J = 8.5 Hz, 2H), 7.12-7.10 (m, 6H), 7.03 (d,
J= 16.5 Hz, 1H), 6.96 (d, J= 16.5 Hz, 1H), 6.91 (s, 1H), 6.66 (d, J = 2.5 Hz, 2H), 6.41 (t, J = 2.5 Hz, 1H), 5.69 (d, J = 8.0 Hz, NH), 4.50-4.45 (m, 1H), 4.37-4.32 (m, 1H), 4.28-4.26 (m, 1H), 3.84 (s, 6H), 3.64-3.50 (m, 2H), 3.28-3.23 (m, 1H), 3.08-3.06 (m, 1H), 1.38 (s, 9H). Mass found [M + H]+ = 832.4。 Yield 62%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 8.18 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.43-7.38 (m, 9H), 7.15 (d, J = 8.5 Hz, 2H), 7.12-7.10 (m, 6H), 7.03 (d,
J= 16.5 Hz, 1H), 6.96 (d, J= 16.5 Hz, 1H), 6.91 (s, 1H), 6.66 (d, J = 2.5 Hz, 2H), 6.41 (t, J = 2.5 Hz, 1H), 5.69 (d, J = 8.0 Hz, NH), 4.50-4.45 (m, 1H), 4.37-4.32 (m, 1H), 4.28-4.26 (m, 1H), 3.84 (s, 6H), 3.64-3.50 (m, 2H), 3.28-3.23 (m, 1H), 3.08-3.06 (m, 1H), 1.38 (s, 9H). Mass found [M + H] + = 832.4.

ジ－ｔｅｒｔ－ブチル（６－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－６－オキソヘキサン－１，５－ジイル）（Ｅ）－ジカルバメート（４ｎ）
４ａと同様の合成手順で２ｎから４ｎを得た。 Di-tert-butyl(6-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-6-oxohexane-1,5-diyl)(E)-dicarbamate (4n)
4n was obtained from 2n by a similar synthetic procedure to 4a.

収率３９％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.62 (brs, NH), 6.41 (t, J = 2.0 Hz, 1H), 5.13 (brs, NH), 4.61 (b
rs, NH), 4.34 (t, J = 5.0 Hz, 2H), 4.07 (s, 1H), 3.84 (s, 6H), 3.69-3.62 (m, 2H), 3.12-3.11 (m, 2H) 1.90-1.83 (m, 1H), 1.67-1.61 (m, 1H), 1.57-1.47 (m, 2H), 1.45-1.42 (m, 18H), 1.40-1.37 (m, 2H). Mass found [M-2Boc+H]+ = 473.0; [M-Boc+H]+= 573.4; [M + H]+ = 673.4, [M + Na]+ = 695.4, [M + K]+= 711.4。 Yield: 39%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.62 (brs, NH), 6.41 (t, J = 2.0 Hz, 1H), 5.13 (brs, NH), 4.61 (b
rs, NH), 4.34 (t, J = 5.0 Hz, 2H), 4.07 (s, 1H), 3.84 (s, 6H), 3.69-3.62 (m, 2H), 3.12-3.11 (m, 2H) 1.90-1.83 (m, 1H), 1.67-1.61 (m, 1H), 1.57-1.47 (m, 2H), 1.45-1.42 (m, 18H), 1.40-1.37 (m, 2H). Mass found [M-2Boc+H] + = 473.0; [M-Boc+H] + = 573.4; [M + H] + = 673.4, [M + Na] + = 695.4, [M + K] + = 711.4.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソ－５－（３－（（２，２，４，６，７－ペンタメチル－２，３－ジヒドロベンゾフラン－５－イル）スルホニル）グアニジノ）ペンタン－２－イル）カルバメート（４ｏ）
４ａと同様の合成手順で２ｏから４ｏを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)pentan-2-yl)carbamate (4o)
4o was obtained from 2o via a similar synthetic procedure to 4a.

収率２９％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.46 (d, J= 8.0 Hz, 2H), 7.39 (brs, NH), 7.13 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 16.5 Hz, 1H), 6.97 (d, J = 16.5 Hz, 1H), 6.65 (d, J = 1.0 Hz, 2H), 6.40 (s, 1H), 6.27 (brs, NH), 5.57 (d, J = 6.0 Hz, NH), 4.33-4.29 (m, 2H), 4.25 (s, 1H), 3.83 (s, 6H), 3.68-3.62 (m, 1H), 3.59-3.55 (m, 1H), 3.30-3.25 (m, 2H), 2.93 (s, 2H), 2.57 (s, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.69-1.55 (m, 4H), 1.44 (s, 6H), 1.42 (s, 9H). Mass found [M + H]+ = 852.3。 Yield: 29%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.46 (d, J = 8.0Hz, 2H), 7.39 (brs, NH), 7.13 (d, J = 9.0Hz, 2H), 7.04 (d, J = 16.5Hz, 1H), 6.97 (d, J = 16.5Hz, 1H), 6.65 (d, J = 1.0Hz, 2H), 6.40 (s, 1H), 6.27 (brs, NH), 5.57 (d, J = 6.0Hz, NH), 4.33-4.29 (m, 2H), 4.25 (s, 1H), 3.83 (s, 6H), 3.68-3.62 (m, 1H), 3.59-3.55 (m, 1H), 3.30-3.25 (m, 2H), 2.93 (s, 2H), 2.57 (s, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.69-1.55 (m, 4H), 1.44 (s, 6H), 1.42 (s, 9H). Mass found [M + H] + = 852.3.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１，４－ジオキソ－４－（トリチルアミノ）ブタン－２－イル）カルバメート（４ｐ）
４ａと同様の合成手順で２ｐから４ｐを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1,4-dioxo-4-(tritylamino)butan-2-yl)carbamate (4p)
4p was obtained from 2p via a similar synthetic procedure to 4a.

収率２８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.50 (d, J= 8.5 Hz, 2H), 7.31-7.23 (m, 11H), 7.20-7.15 (m, 6H), 7.06 (d, J = 16.5 Hz, 1H), 6.99 (brs, NH), 6.98 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 6.19 (brs, NH), 4.46-4.42 (m, 1H), 4.31-4.19 (m, 2H), 3.84 (s, 6H), 3.64-3.51 (m, 2H), 3.11-3.09 (m, 1H), 2.60-2.57 (m, 1H), 1.42 (s, 9H). Mass found [M + H]+ = 799.5。 Yield: 28%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.50 (d, J= 8.5 Hz, 2H), 7.31-7.23 (m, 11H), 7.20-7.15 (m, 6H), 7.06 (d, J = 16.5 Hz, 1H), 6.99 (brs, NH), 6.98 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 6.19 (brs, NH), 4.46-4.42 (m, 1H), 4.31-4.19 (m, 2H), 3.84 (s, 6H), 3.64-3.51 (m, 2H), 3.11-3.09 (m, 1H), 2.60-2.57 (m, 1H), 1.42 (s, 9H). Mass found [M + H] + = 799.5.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１，５－ジオキソ－５－（トリチルアミノ）ペンタン－２－イル）カルバメート（４ｑ）
４ａと同様の合成手順で２ｑから４ｑを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1,5-dioxo-5-(tritylamino)pentan-2-yl)carbamate (4q)
4q was obtained from 2q by a synthetic procedure similar to that of 4a.

収率２７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.30-7.28 (m, 15H), 7.15 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 16.5 Hz, 1H), 6.98 (d, J = 16.5 Hz, 1H), 6.76 (brs, NH), 6.67 (s, 2H), 6.62 (brs, NH), 6.41 (s, 1H), 5.53 (brs, NH), 4.27-4.26 (m, 1H), 4.15-4.12 (m, 1H), 3.99-3.96 (m, 1H), 3.84 (s, 6H), 3.56-3.54 (m, 1H), 3.47-3.46 (m, 1H), 2.53-2.50 (m, 1H), 2.45-2.40 (m, 1H), 2.04-1.87 (m, 2H), 1.42 (s, 9H). Mass found [M + H]+ = 814.3。 Yield: 27%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.48 (d, J = 8.5 Hz, 2H), 7.30-7.28 (m, 15H), 7.15 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 16.5 Hz, 1H), 6.98 (d, J = 16.5 Hz, 1H), 6.76 (brs, NH), 6.67 (s, 2H), 6.62 (brs, NH), 6.41 (s, 1H), 5.53 (brs, NH), 4.27-4.26 (m, 1H), 4.15-4.12 (m, 1H), 3.99-3.96 (m, 1H), 3.84 (s, 6H), 3.56-3.54 (m, 1H), 3.47-3.46 (m, 1H), 2.53-2.50 (m, 1H), 2.45-2.40 (m, 1H), 2.04-1.87 (m, 2H), 1.42 (s, 9H). Mass found [M + H] + = 814.3.

ｔｅｒｔ－ブチル（Ｅ）－３－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－４－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－４－オキソブタノエート（４ｒ）
４ａと同様の合成手順で２ｒから４ｒを得た。 tert-Butyl (E)-3-((tert-butoxycarbonyl)amino)-4-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-oxobutanoate (4r)
4r was obtained from 2r via a similar synthetic procedure to 4a.

収率４８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.07 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.93 (brs,
NH), 6.66 (d, J = 2.0 Hz, 2H), 6.41 (s, 1H), 5.68 (brs, NH), 4.47 (s, 1H), 4.32
(t, J= 5.5 Hz, 2H), 3.83 (s, 6H), 3.64-3.63 (m, 2H), 2.90 (dd, J = 5.0, 17.5 Hz, 1H), 2.62 (dd, J = 6.5, 17.0 Hz, 1H), 1.46 (s, 9H), 1.45 (s, 9H). Mass found [M-Boc-tBu+H]+= 460.1; [M + H]+ = 616.3; [M + Na]+ = 638.3。 Yield: 48%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.51 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.07 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.93 (brs,
NH), 6.66 (d, J = 2.0 Hz, 2H), 6.41 (s, 1H), 5.68 (brs, NH), 4.47 (s, 1H), 4.32
(t, J= 5.5 Hz, 2H), 3.83 (s, 6H), 3.64-3.63 (m, 2H), 2.90 (dd, J = 5.0, 17.5 Hz, 1H), 2.62 (dd, J = 6.5, 17.0 Hz, 1H), 1.46 (s, 9H), 1.45 (s, 9H). Mass found [M-Boc-tBu+H] + = 460.1; [M + H] + = 616.3; [M + Na] + = 638.3.

ｔｅｒｔ－ブチル（Ｅ）－４－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－５－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－５－オキソペンタノエート（４ｓ）
４ａと同様の合成手順で２ｓから４ｓを得た。 tert-Butyl (E)-4-((tert-butoxycarbonyl)amino)-5-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-5-oxopentanoate (4s)
4s was obtained from 2s via a similar synthetic procedure to 4a.

収率５５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.76 (brs,
NH), 6.66 (d, J = 2.0 Hz, 2H), 6.41 (d, J = 2.0 Hz, 1H), 5.29 (brs, NH), 4.33 (t, J = 5.5 Hz, 2H), 4.14 (s, 1H), 3.83 (s, 6H), 3.69-3.63 (m, 2H), 2.46-2.40 (m,
1H), 2.35-2.29 (m, 1H), 2.13-2.06 (m, 1H), 1.94-1.87 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H). Mass found [M - Boc - OtBu + H]+ = 456.1, [M - Boc - tBu + H]+= 474.0; [M + H]+ = 630.4; [M + Na]+ = 652.3。 Yield: 55%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.76 (brs,
NH), 6.66 (d, J = 2.0 Hz, 2H), 6.41 (d, J = 2.0 Hz, 1H), 5.29 (brs, NH), 4.33 (t, J = 5.5 Hz, 2H), 4.14 (s, 1H), 3.83 (s, 6H), 3.69-3.63 (m, 2H), 2.46-2.40 (m,
1H), 2.35-2.29 (m, 1H), 2.13-2.06 (m, 1H), 1.94-1.87 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H). Mass found [M-Boc-OtBu + H] + = 456.1, [M-Boc-tBu + H] + = 474.0; [M + H] + = 630.4; [M + Na] + = 652.3.

（Ｅ）－２－（２－アミノアセトアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ａ）
ＤＣＭ（１０ｍＬ）中の化合物４ａ（７２６ｍｇ、１．５ｍｍｏｌ）の撹拌溶液に１，４－ジオキサン（７．２５ｍＬ）中の４Ｍ ＨＣｌを加え、混合物を室温で３時間撹拌した。その後、反応溶液を蒸発させ、分取ＨＰＬＣ精製に供した（バッファーとしてＴＦＡ、詳細なグラジエント溶出は下記情報を参照のこと）。その後、水性画分を濃塩酸数滴で処理し、凍結乾燥して化合物５ａ（６０２ｍｇ，収率９５％）を白色固体として得た。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.5 Hz, 2H), 6.40 (t, J= 2.5 Hz, 1H), 4.33 (t, J= 5.5 Hz, 2H), 3.80 (s, 6H), 3.71 (s, 2H), 3.61 (t, J = 5.5 Hz, 2H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 166.26, 161.12, 153.66, 150.50, 139.18, 135.47, 128.95, 127.43, 127.19, 120.96, 104.22, 99.60, 66.73, 54.39, 40.09, 38.13; Mass found [M - HCl + H]+ = 402.2; [M - HCl + Na]+= 424.2; [M - HCl + K]+ = 440.1; [2M - 2HCl + H]+ = 802.3; [2M - 2HCl + Na]+ = 824.4。 (E)-2-(2-aminoacetamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5a)
To a stirred solution of compound 4a (726 mg, 1.5 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (7.25 mL) and the mixture was stirred at room temperature for 3 h. The reaction solution was then evaporated and subjected to preparative HPLC purification (TFA as buffer, detailed gradient elution see information below). The aqueous fraction was then treated with a few drops of concentrated hydrochloric acid and lyophilized to give compound 5a (602 mg, 95% yield) as a white solid. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.07 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.5Hz, 2H), 6.40 (t, J= 2.5Hz, 1H), 4.33 (t, J= 5.5Hz, 2H), 3.80 (s, 6H), 3.71 (s, 2H), 3.61 (t, J = 5.5Hz, 2H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 166.26, 161.12, 153.66, 150.50, 139.18, 135.47, 128.95, 127.43, 127.19, 120.96, 104.22, 99.60, 66.73, 54.39, 40.09, 38.13; Mass found [M - HCl + H] + = 402.2; [M - HCl + Na] + = 424.2; [M - HCl + K] + = 440.1; [2M - 2HCl + H] + = 802.3; [2M - 2HCl + Na] + = 824.4.

カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３ Ｃ１８，５ｕｍ，３０＊２５０ｍｍ
流量：３８ｍｌ／分
溶媒Ａ：Ｈ２Ｏ中１０％ＡＣＮ＋０．１％ＴＦＡ
溶媒Ｂ：Ｈ２Ｏ中９０％ＡＣＮ＋０．１％ＴＦＡ
グラジエント： Column: Inertsil ODS-3 C18, 5um, 30*250mm
Flow rate: 38 ml/min Solvent A: 10% ACN + 0.1% TFA in H2O
Solvent B: 90% ACN + 0.1% TFA in H2O
Gradient:

（Ｅ）－２－（２－アミノプロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｂ）
５ａと同様の合成手順で４ｂから５ｂを得た。 (E)-2-(2-aminopropanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5b)
5b was obtained from 4b via a similar synthetic procedure to 5a.

収率９８％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.37-4.31 (m, 2H), 3.97-3.93 (m, 1H), 3.80 (s, 6H), 3.67-3.62 (m, 1H), 3.59-3.54 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 169.97, 161.14, 153.67, 150.51, 139.18, 135.48, 128.96, 127.42, 127.18, 120.95, 104.21, 99.59, 66.62, 54.39, 48.86, 38.22, 16.24;
Mass found [M - HCl + H]+ = 416.2; [M - HCl + Na]+ = 438.2; [2M - HCl + H]+ = 830.5; [2M - 2HCl + Na]+ = 852.4。 Yield: 98%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 8.5Hz, 2H), 7.17 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.37-4.31 (m, 2H), 3.97-3.93 (m, 1H), 3.80 (s, 6H), 3.67-3.62 (m, 1H), 3.59-3.54 (m, 1H), 1.50 (d, J = 7.0Hz, 3H); 13C -NMR (CD3OD , 125MHz), δ(ppm): 169.97, 161.14, 153.67, 150.51, 139.18, 135.48, 128.96, 127.42, 127.18, 120.95, 104.21, 99.59, 66.62, 54.39, 48.86, 38.22, 16.24;
Mass found [M - HCl + H] + = 416.2; [M - HCl + Na] + = 438.2; [2M - HCl + H] + = 830.5; [2M - 2HCl + Na] + = 852.4.

（Ｅ）－２－（２－アミノ－３－メチルブタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｃ）
５ａと同様の合成手順で４ｃから５ｃを得た。 (E)-2-(2-amino-3-methylbutanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5c)
5c was obtained from 4c via a similar synthetic procedure to 5a.

収率９９％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.43 (d, J= 7.0 Hz, 2H), 7.13 (d, J= 7.0 Hz, 2H), 6.99-6.88 (m, 2H), 6.60 (s, 2H), 6.36 (s, 1H), 4.37-4.30 (m, 2H), 4.15 (brs, 1H), 3.77 (s, 6H), 3.50 (brs, 1H), 2.98-2.92 (m, 2H), 2.34-2.33 (m, 1H), 1.10-1.05 (m, 6H); 13C- NMR (CDCl3, 125 MHz), δ(ppm): 168.94, 160.94, 153.59, 150.23, 138.99, 135.32, 129.23, 127.78, 127.55, 121.33, 104.61, 100.11, 66.81, 58.91, 55.32, 38.42, 30.18, 18.60, 18.16; Mass found [M - HCl + H]+ = 444.1; [M - HCl + Na]+= 466.1。 Yield: 99%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.43 (d, J= 7.0 Hz, 2H), 7.13 (d, J= 7.0 Hz, 2H), 6.99-6.88 (m, 2H), 6.60 (s, 2H), 6.36 (s, 1H), 4.37-4.30 (m, 2H), 4.15 (brs, 1H), 3.77 (s, 6H), 3.50 (brs, 1H), 2.98-2.92 (m, 2H), 2.34-2.33 (m, 1H), 1.10-1.05 (m, 6H); 13C -NMR ( CDCl3 , 125 MHz), δ(ppm): 168.94, 160.94, 153.59, 150.23, 138.99, 135.32, 129.23, 127.78, 127.55, 121.33, 104.61, 100.11, 66.81, 58.91, 55.32, 38.42, 30.18, 18.60, 18.16; Mass found [M - HCl + H] + = 444.1; [M - HCl + Na] + = 466.1.

（Ｅ）－２－（２－アミノ－４－メチルペンタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｄ）
５ａと同様の合成手順で４ｄから５ｄを得た。 (E)-2-(2-amino-4-methylpentanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5d)
5d was obtained from 4d by a similar synthetic procedure to 5a.

収率９５％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.40-4.30 (m, 2H), 3.88-3.86 (m, 1H), 3.80 (s, 6H), 3.72-3.67 (m, 1H), 3.55-3.50 (m, 1H), 1.75-1.67 (m, 3H), 1.00 (t, J = 5.5 Hz, 6H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 169.66, 161.15, 153.61, 150.51, 139.19, 135.49, 128.98, 127.42, 127.18, 120.92, 104.23, 99.61, 66.53, 54.39, 51.70, 43.34, 38.21, 24.05, 21.61, 20.82; Mass found [M - HCl + H]+= 457.2; [2M -
2HCl + H]+ = 913.3。 Yield: 95%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 8.5Hz, 2H), 7.18 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.40-4.30 (m, 2H), 3.88-3.86 (m, 1H), 3.80 (s, 6H), 3.72-3.67 (m, 1H), 3.55-3.50 (m, 1H), 1.75-1.67 (m, 3H), 1.00 (t, J = 5.5 Hz, 6H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 169.66, 161.15, 153.61, 150.51, 139.19, 135.49, 128.98, 127.42, 127.18, 120.92, 104.23, 99.61, 66.53, 54.39, 51.70, 43.34, 38.21, 24.05, 21.61, 20.82; Mass found [M - HCl + H] + = 457.2; [2M -
2HCl + H] + = 913.3.

（Ｅ）－２－（２－アミノ－３－メチルペンタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｅ）
５ａと同様の合成手順で４ｅから５ｅを得た。 (E)-2-(2-amino-3-methylpentanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5e)
5e was obtained from 4e via a similar synthetic procedure to 5a.

収率９８％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.59 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.40-4.36 (m, 1H), 4.33-4.28 (m, 1H), 3.80 (s, 6H), 3.78-3.72 (m, 2H), 3.52-3.47 (m, 1H), 1.95-1.92 (m, 1H), 1.63-1.58 (m, 1H), 1.28-1.22 (m, 1H), 1.05 (d, J = 7.0 Hz, 3H), 0.98 (t, J= 7.0 Hz, 3H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.41, 161.15, 153.56, 150.50, 139.19, 135.49,
128.97, 127.43, 127.18, 120.92, 104.23, 99.61, 66.60, 57.68, 54.39, 38.05, 36.62, 24.19, 13.66, 10.32; Mass found [M - HCl + H]+ = 457.2; [2M - 2HCl + H]+ = 91
3.3。 Yield: 98%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.59 (d, J= 8.5Hz, 2H), 7.17 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.40-4.36 (m, 1H), 4.33-4.28 (m, 1H), 3.80 (s, 6H), 3.78-3.72 (m, 2H), 3.52-3.47 (m, 1H), 1.95-1.92 (m, 1H), 1.63-1.58 (m, 1H), 1.28-1.22 (m, 1H), 1.05 (d, J = 7.0 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H); 13C -NMR (CD 3 OD, 125 MHz), δ(ppm): 168.41, 161.15, 153.56, 150.50, 139.19, 135.49,
128.97, 127.43, 127.18, 120.92, 104.23, 99.61, 66.60, 57.68, 54.39, 38.05, 36.62, 24.19, 13.66, 10.32; Mass found [M - HCl + H] + = 457.2; [2M - 2HCl + H] + = 91
3.3.

（Ｅ）－２－（２－アミノ－４－（メチルチオ）ブタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｆ）
５ａと同様の合成手順で４ｆから５ｆを得た。 (E)-2-(2-amino-4-(methylthio)butanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5f)
5f was obtained from 4f via a similar synthetic procedure to 5a.

収率８５％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.59 (d, J= 8.5 Hz, 2H), 7.19 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.42-4.38 (m, 1H), 4.33-4.28 (m, 1H), 3.99 (t, J = 6.5 Hz, 1H), 3.80 (s, 6H), 3.78-3.73 (m, 1H), 3.52-3.47 (m, 1H), 2.60
(t, J = 7.5 Hz, 2H), 2.18-2.11 (m, 2H), 2.09 (s, 3H); 13C-NMR (CD3OD, 125 MHz),
δ(ppm): 168.70, 161.14, 153.62, 150.49, 139.18, 135.49, 128.97, 127.43, 127.18, 120.99, 104.21, 99.60, 66.58, 54.39, 52.32, 38.21, 30.70, 28.33, 13.69; Mass found [M - HCl + H]+ = 476.2; [M - HCl + Na]+= 498.2; [2M - HCl + H]+ = 950.4。 Yield: 85%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.59 (d, J= 8.5Hz, 2H), 7.19 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.42-4.38 (m, 1H), 4.33-4.28 (m, 1H), 3.99 (t, J = 6.5Hz, 1H), 3.80 (s, 6H), 3.78-3.73 (m, 1H), 3.52-3.47 (m, 1H), 2.60
(t, J = 7.5 Hz, 2H), 2.18-2.11 (m, 2H), 2.09 (s, 3H); 13C -NMR ( CD3OD , 125 MHz),
δ(ppm): 168.70, 161.14, 153.62, 150.49, 139.18, 135.49, 128.97, 127.43, 127.18, 120.99, 104.21, 99.60, 66.58, 54.39, 52.32, 38.21, 30.70, 28.33, 13.69; Mass found [M - HCl + H] + = 476.2; [M - HCl + Na] + = 498.2; [2M - HCl + H] + = 950.4.

（Ｅ）－２－（２－アミノ－３－ヒドロキシプロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｇ）
５ａと同様の合成手順で４ｇから５ｇを得た。 (E)-2-(2-amino-3-hydroxypropanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5 g)
5g was obtained from 4g by the same synthetic procedure as for 5a.

収率７６％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.34 (t, J= 5.0 Hz, 2H), 3.98-3.94 (m, 2H), 3.86-3.81 (m, 1H), 3.80 (s, 6H), 3.62-3.60 (m, 2H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 167.21, 161.13, 153.69, 150.51, 139.20, 135.47, 128.96, 127.44, 127.19, 120.97, 104.23, 99.61, 66.64, 60.30, 54.93, 54.40, 38.29; Mass found [M - HCl
+ H]+ = 431.2; [2M - 2HCl + H]+ = 861.2。 Yield: 76%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.07 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.34 (t, J= 5.0Hz, 2H), 3.98-3.94 (m, 2H), 3.86-3.81 (m, 1H), 3.80 (s, 6H), 3.62-3.60 (m, 2H); 13C -NMR ( CD3OD , 125 MHz), δ(ppm): 167.21, 161.13, 153.69, 150.51, 139.20, 135.47, 128.96, 127.44, 127.19, 120.97, 104.23, 99.61, 66.64, 60.30, 54.93, 54.40, 38.29; Mass found [M - HCl
[2M - 2HCl + H] + = 431.2; [2M - 2HCl + H] + = 861.2.

（Ｅ）－２－（２－アミノ－３－ヒドロキシブタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｈ）
５ａと同様の合成手順で４ｈから５ｈを得た。 (E)-2-(2-amino-3-hydroxybutanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5h)
5h was obtained from 4h via a similar synthetic procedure to 5a.

収率７４％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.0 Hz, 1H), 7.07 (d, J= 16.0 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.38-4.31 (m, 2H), 4.06-4.01 (m, 1H), 3.80 (s, 6H), 3.72-3.65 (m, 2H), 3.58-3.53 (m, 1H), 1.31 (d, J = 6.0 Hz, 3H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 167.54, 161.14, 153.58, 150.50, 139.19, 135.49, 128.97, 127.43, 127.18, 120.95, 104.23, 99.61, 66.61, 65.97, 59.12, 54.40, 38.14,
18.91; Mass found [M - HCl + H]+ = 445.2; [2M - 2HCl + H]+= 889.2。 Yield: 74%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 8.5Hz, 2H), 7.17 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.0Hz, 1H), 7.07 (d, J= 16.0Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.38-4.31 (m, 2H), 4.06-4.01 (m, 1H), 3.80 (s, 6H), 3.72-3.65 (m, 2H), 3.58-3.53 (m, 1H), 1.31 (d, J = 6.0Hz, 3H); 13C -NMR (CD3OD , 125MHz), δ(ppm): 167.54, 161.14, 153.58, 150.50, 139.19, 135.49, 128.97, 127.43, 127.18, 120.95, 104.23, 99.61, 66.61, 65.97, 59.12, 54.40, 38.14,
18.91; Mass found [M - HCl + H] + = 445.2; [2M - 2HCl + H] + = 889.2.

（Ｅ）－２－（２－アミノ－３－メルカプトプロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｉ）
ＤＣＭ（１５ｍＬ）中の化合物４ｉ（７６０ｍｇ，１．０ｍｍｏｌ）の撹拌溶液に、ＴＦＡ（１４．９ｍＬ）およびトリイソプロピルシラン（ＴＩＰＳ，７９０ｕＬ，３．９ｍｍｏｌ）を加え、得られた混合物を室温で２時間撹拌した。その後、反応溶液を蒸発させ、分取ＨＰＬＣによる精製に供した（バッファーとしてＴＦＡ、詳細なグラジエント溶出は下記情報を参照のこと）。その後、水性画分を濃塩酸数滴で処理し、凍結乾燥して化合物５ｉ（３５４ｍｇ，７６％）を白色固体として得た。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 1.5 Hz, 2H), 6.40 (s, 1H), 4.41-4.37 (m, 1H), 4.34-4.30 (m, 1H), 4.05 (t, J = 5.5 Hz, 1H), 3.80 (s, 6H), 3.74-3.69 (m, 1H)
, 3.57-3.52 (m, 1H), 3.06 (dd, J = 5.5, 14.5 Hz, 1H), 2.98 (dd, J = 6.5, 15.0 Hz, 1H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 167.31, 161.14, 153.63, 150.50, 139.19,
135.50, 128.97, 127.43, 127.18, 120.97, 104.23, 99.62, 66.61, 54.69, 54.39, 38.28, 24.96; Mass found [M - HCl + H]+= 448.2; [M - HCl + Na]+ = 470.2; [2M - 2HCl
+ H]+ = 894.4。 (E)-2-(2-amino-3-mercaptopropanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5i)
To a stirred solution of compound 4i (760 mg, 1.0 mmol) in DCM (15 mL) was added TFA (14.9 mL) and triisopropylsilane (TIPS, 790 uL, 3.9 mmol), and the resulting mixture was stirred at room temperature for 2 h. The reaction solution was then evaporated and subjected to purification by preparative HPLC (TFA as buffer, detailed gradient elution see information below). The aqueous fraction was then treated with a few drops of concentrated hydrochloric acid and lyophilized to give compound 5i (354 mg, 76%) as a white solid. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 1.5Hz, 2H), 6.40 (s, 1H), 4.41-4.37 (m, 1H), 4.34-4.30 (m, 1H), 4.05 (t, J = 5.5Hz, 1H), 3.80 (s, 6H), 3.74-3.69 (m, 1H).
, 3.57-3.52 (m, 1H), 3.06 (dd, J = 5.5, 14.5 Hz, 1H), 2.98 (dd, J = 6.5, 15.0 Hz, 1H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 167.31, 161.14, 153.63, 150.50, 139.19,
135.50, 128.97, 127.43, 127.18, 120.97, 104.23, 99.62, 66.61, 54.69, 54.39, 38.28, 24.96; Mass found [M - HCl + H] + = 448.2; [M - HCl + Na] + = 470.2; [2M - 2HCl
+ H] + = 894.4.

カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３ Ｃ１８，５ｕｍ，３０＊２５０ｍｍ
流量：３８ｍＬ／分
溶媒Ａ：Ｈ２Ｏ中１０％ＡＣＮ＋０．１％ＴＦＡ
溶媒Ｂ：Ｈ２Ｏ中９０％ＡＣＮ＋０．１％ＴＦＡ
グラジエント： Column: Inertsil ODS-3 C18, 5um, 30*250mm
Flow rate: 38 mL/min Solvent A: 10% ACN + 0.1% TFA in H2O
Solvent B: 90% ACN + 0.1% TFA in H2O
Gradient:

（Ｅ）－２－（２－アミノ－３－フェニルプロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｊ）
５ａと同様の合成手順で４ｊから５ｊを得た。 (E)-2-(2-amino-3-phenylpropanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5j)
5j was obtained from 4j via a similar synthetic procedure to 5a.

収率９０％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.38-7.35 (m, 2H), 7.31-7.29 (m, 3H), 7.18 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 16.5 Hz, 1H), 7.07 (d, J = 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (d, J= 2.0 Hz, 1H),
4.24-4.20 (m, 2H), 4.07 (t, J = 7.5 Hz, 1H), 3.80 (s, 6H), 3.65-3.60 (m, 1H), 3.48-3.44 (m, 1H), 3.19 (dd, J= 7.5, 14.0 Hz, 1H), 3.09 (dd, J = 7.5, 14.0 Hz, 1H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.49, 161.14, 153.51, 150.50, 139.19, 135.49, 134.15, 129.12, 128.98,128.71, 127.48, 127.42, 127.19, 120.92, 104.23, 99.61, 66.66, 54.40, 54.40, 38.02, 37.29; Mass found [M - HCl + H]+= 491.3; [M - HCl + Na]+ = 513.2。 Yield 90%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 8.5Hz, 2H), 7.38-7.35 (m, 2H), 7.31-7.29 (m, 3H), 7.18 (d, J = 8.5Hz, 2H), 7.14 (d, J = 16.5Hz, 1H), 7.07 (d, J = 16.5Hz, 1H), 6.71 (d, J = 2.0Hz, 2H), 6.40 (d, J = 2.0Hz, 1H),
4.24-4.20 (m, 2H), 4.07 (t, J = 7.5 Hz, 1H), 3.80 (s, 6H), 3.65-3.60 (m, 1H), 3.48-3.44 (m, 1H), 3.19 (dd, J = 7.5, 14.0 Hz, 1H), 3.09 (dd, J = 7.5, 14.0 Hz, 1H); 13C -NMR (CD 3 OD, 125 MHz), δ(ppm): 168.49, 161.14, 153.51, 150.50, 139.19, 135.49, 134.15, 129.12, 128.98,128.71, 127.48, 127.42, 127.19, 120.92, 104.23, 99.61, 66.66, 54.40, 54.40, 38.02, 37.29; Mass found [M - HCl + H] + = 491.3; [M - HCl + Na] + = 513.2.

（Ｅ）－２－（２－アミノ－３－（４－ヒドロキシフェニル）プロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｋ）
５ａと同様の合成手順で４ｋから５ｋを得た。 (E)-2-(2-amino-3-(4-hydroxyphenyl)propanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5k)
5k was obtained from 4k via a similar synthetic procedure to 5a.

収率８４％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.57 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.11 (d, J= 9.0 Hz, 2H), 7.06 (d, J=
16.5 Hz, 1H), 6.79 (d, J= 9.0 Hz, 2H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 4.27-4.24 (m, 2H), 4.00 (t, J = 7.5 Hz, 1H), 3.80 (s, 6H), 3.66-3.61 (m, 1H), 3.50-3.45 (m, 1H), 3.10 (dd, J = 7.0, 14.0 Hz, 1H), 2.98 (dd, J = 7.0, 14.0 Hz, 1H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.67, 161.14, 156.89, 153.57, 150.51, 139.19, 135.47, 130.22, 128.96, 127.43, 127.18, 124.55, 121.00, 115.42, 104.22, 99.61, 66.68, 54.61, 54.39, 38.05, 36.54; Mass found [M - HCl + H]+ = 507.2; [2M - 2
HCl + H]+ = 1013.2。 Yield: 84%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.57 (d, J= 8.5Hz, 2H), 7.18 (d, J= 8.5Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.11 (d, J= 9.0Hz, 2H), 7.06 (d, J=
16.5 Hz, 1H), 6.79 (d, J= 9.0 Hz, 2H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 4.27-4.24 (m, 2H), 4.00 (t, J = 7.5 Hz, 1H), 3.80 (s, 6H), 3.66-3.61 (m, 1H), 3.50-3.45 (m, 1H), 3.10 (dd, J = 7.0, 14.0 Hz, 1H), 2.98 (dd, J = 7.0, 14.0 Hz, 1H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 168.67, 161.14, 156.89, 153.57, 150.51, 139.19, 135.47, 130.22, 128.96, 127.43, 127.18, 124.55, 121.00, 115.42, 104.22, 99.61, 66.68, 54.61, 54.39, 38.05, 36.54; Mass found [M - HCl + H] + = 507.2; [2M - 2
HCl + H] + = 1013.2.

（Ｅ）－２－（２－アミノ－３－（１Ｈ－インドール－３－イル）プロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｌ）
５ａと同様の合成手順で４ｌから５ｌを得た。 (E)-2-(2-amino-3-(1H-indol-3-yl)propanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5l)
5l was obtained from 4l via a similar synthetic procedure to 5a.

収率７８％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.65 (d, J= 8.0 Hz, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 8.5 Hz, 1H), 7.23 (s, 1H), 7.17-7.15 (m, 3H), 7.12
(d, J = 16.5 Hz, 1H), 7.10 (d, J = 16.5 Hz, 1H), 7.06-7.03 (m, 1H), 6.70 (d, J=
2.0 Hz, 2H), 6.40 (s, 1H), 4.25-4.21 (m, 1H), 4.18-4.10 (m, 2H), 3.80 (s, 6H), 3.60-3.55 (m, 1H), 3.50-3.45 (m, 1H), 3.39 (dd, J = 6.5, 15.0 Hz, 1H), 3.25 (dd,
J = 8.0, 15.0 Hz, 1H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 169.10, 161.13, 153.54, 150.50, 139.18, 136.88, 135.47, 128.95, 127.41, 127.17, 126.91, 124.19, 121.52, 120.95, 118.88, 117.69, 111.26, 106.58, 104.22, 99.61, 66.53, 54.40, 54.38, 53.74, 38.17, 27.51; Mass found [M - HCl + H]+= 530.3; [2M - 2HCl + H]+ = 1059.4。 Yield 78%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.65 (d, J= 8.0Hz, 1H), 7.55 (d, J= 8.0Hz, 2H), 7.39 (d, J= 8.5Hz, 1H), 7.23 (s, 1H), 7.17-7.15 (m, 3H), 7.12
(d, J = 16.5 Hz, 1H), 7.10 (d, J = 16.5 Hz, 1H), 7.06-7.03 (m, 1H), 6.70 (d, J=
2.0 Hz, 2H), 6.40 (s, 1H), 4.25-4.21 (m, 1H), 4.18-4.10 (m, 2H), 3.80 (s, 6H), 3.60-3.55 (m, 1H), 3.50-3.45 (m, 1H), 3.39 (dd, J = 6.5, 15.0 Hz, 1H), 3.25 (dd,
J = 8.0, 15.0 Hz, 1H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 169.10, 161.13, 153.54, 150.50, 139.18, 136.88, 135.47, 128.95, 127.41, 127.17, 126.91, 124.19, 121.52, 120.95, 118.88, 117.69, 111.26, 106.58, 104.22, 99.61, 66.53, 54.40, 54.38, 53.74, 38.17, 27.51; Mass found [M - [HCl + H] + = 530.3; [2M - 2HCl + H] + = 1059.4.

（Ｅ）－２－（２－アミノ－３－（１Ｈ－イミダゾール－２－イル）プロパンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート二塩酸塩（５ｍ）
５ａと同様の合成手順で４ｍから５ｍを得た。 (E)-2-(2-amino-3-(1H-imidazol-2-yl)propanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate dihydrochloride (5m)
5m was obtained from 4m by a similar synthetic procedure to 5a.

収率８２％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 8.90 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.53 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 16.5 Hz, 1H), 7.08 (d, J = 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.41 (t, J= 2.0 Hz, 1H), 4.36-4.32 (m, 1H), 4.31-4.27 (m, 2H), 3.81 (s, 6H), 3.71-3.66 (m, 1H), 3.55-3.50 (m, 1H), 3.42-3.35 (m, 2H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 167.46, 161.15, 153.55, 150.48, 139.17, 135.54, 134.43, 129.00, 127.40, 127.18, 126.62, 121.05, 118.36, 104.23, 99.61, 66.58, 54.40, 51.96, 38.30, 26.20; Mass found [M - HCl + H]+= 482.2; [M - HCl + Na]+ = 504.1; [2M - 2HCl + H]+ = 962.3。 Yield: 82%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 8.90 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.53 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 16.5 Hz, 1H), 7.08 (d, J = 16.5 Hz, 1H), 6.71 (d, J = 2.0 Hz, 2H), 6.41 (t, J = 2.0 Hz, 1H), 4.36-4.32 (m, 1H), 4.31-4.27 (m, 2H), 3.81 (s, 6H), 3.71-3.66 (m, 1H), 3.55-3.50 (m, 1H), 3.42-3.35 (m, 2H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 167.46, 161.15, 153.55, 150.48, 139.17, 135.54, 134.43, 129.00, 127.40, 127.18, 126.62, 121.05, 118.36, 104.23, 99.61, 66.58, 54.40, 51.96, 38.30, 26.20; Mass found [M - HCl + H] + = 482.2; [M - HCl + Na] + = 504.1; [2M - 2HCl + H] + = 962.3.

（Ｅ）－２－（２，６－ジアミノヘキサンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート二塩酸塩（５ｎ）
５ａと同様の合成手順で４ｎから５ｎを得た。 (E)-2-(2,6-diaminohexanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate dihydrochloride (5n)
5n was obtained from 4n by a similar synthetic procedure to 5a.

収率７８％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.60 (d, J= 8.5 Hz, 2H), 7.20 (d, J= 8.5 Hz, 2H), 7.16 (d, J= 16.5 Hz, 1H), 7.09 (d, J= 16.5 Hz, 1H), 6.72 (d, J= 2.0 Hz, 2H), 6.41 (s, 1H), 4.42-4.38 (m, 1H), 4.35-4.30 (m, 1H), 3.93 (t, J = 6.5 Hz, 1H), 3.80 (s, 6H), 3.75-3.70 (m, 1H), 3.56-3.51 (m, 1H), 2.93 (t, J = 8.0 Hz, 2H), 1.97-1.87 (m, 2H), 1.75-1.69 (m, 2H), 1.56-1.50 (m, 2H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.97, 161.15, 153.63, 150.50, 139.18, 135.54, 129.01, 127.41, 127.21, 121.03, 104.23, 99.60, 66.68, 54.42, 54.39, 52.81, 38.88, 38.17, 30.66, 26.71, 21.44; Mass found [M - 2HCl + H]+= 472.2。 Yield: 78%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.60 (d, J= 8.5Hz, 2H), 7.20 (d, J= 8.5Hz, 2H), 7.16 (d, J= 16.5Hz, 1H), 7.09 (d, J= 16.5Hz, 1H), 6.72 (d, J= 2.0Hz, 2H), 6.41 (s, 1H), 4.42-4.38 (m, 1H), 4.35-4.30 (m, 1H), 3.93 (t, J = 6.5Hz, 1H), 3.80 (s, 6H), 3.75-3.70 (m, 1H), 3.56-3.51 (m, 1H), 2.93 (t, J = 8.0 Hz, 2H), 1.97-1.87 (m, 2H), 1.75-1.69 (m, 2H), 1.56-1.50 (m, 2H); 13C -NMR ( CD3OD , 125 MHz), δ(ppm): 168.97, 161.15, 153.63, 150.50, 139.18, 135.54, 129.01, 127.41, 127.21, 121.03, 104.23, 99.60, 66.68, 54.42, 54.39, 52.81, 38.88, 38.17, 30.66, 26.71, 21.44; Mass found [M - 2HCl + H] + = 472.2.

（Ｅ）－２－（２－アミノ－５－グアニジノペンタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート二塩酸塩（５ｏ）
５ｉと同様の合成手順で４ｏから５ｏを得た。 (E)-2-(2-amino-5-guanidinopentanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate dihydrochloride (5o)
5o was obtained from 4o via a similar synthetic procedure to 5i.

収率６４％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 7.5 Hz, 2H), 7.19 (d, J= 7.5 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.06 (d, J= 16.5 Hz, 1H), 6.70 (s, 2H), 6.39 (s, 1H), 4.37-4.33 (m, 2H), 3.96 (s, 1H), 3.79 (s, 6H), 3.72-3.69 (m, 1H), 3.60-3.55 (m, 1H), 3.22 (s, 2H), 1.94 (s, 2H), 1.71 (s, 2H); 13C-NMR (CD3OD,
125 MHz), δ(ppm): 168.87, 161.12, 157.19, 153.70, 150.49, 139.18, 135.50, 128.98, 127.43, 127.22, 121.05, 104.24, 99.63, 66.69, 54.42, 52.64, 40.43, 38.21, 28.31, 23.92; Mass found [M - 2HCl + H]+ = 500.1。 Yield: 64%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 7.5Hz, 2H), 7.19 (d, J= 7.5Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.06 (d, J= 16.5Hz, 1H), 6.70 (s, 2H), 6.39 (s, 1H), 4.37-4.33 (m, 2H), 3.96 (s, 1H), 3.79 (s, 6H), 3.72-3.69 (m, 1H), 3.60-3.55 (m, 1H), 3.22 (s, 2H), 1.94 (s, 2H), 1.71 (s, 2H); 13 C-NMR (CD 3 OD,
125 MHz), δ(ppm): 168.87, 161.12, 157.19, 153.70, 150.49, 139.18, 135.50, 128.98, 127.43, 127.22, 121.05, 104.24, 99.63, 66.69, 54.42, 52.64, 40.43, 38.21, 28.31, 23.92; Mass found [M - 2HCl + H] + = 500.1.

（Ｅ）－２－（２，４－ジアミノ－４－オキソブタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｐ）
５ｉと同様の合成手順で４ｐから５ｐを得た。 (E)-2-(2,4-diamino-4-oxobutanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5p)
5p was obtained from 4p via a similar synthetic procedure to 5i.

収率６８％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.59 (d, J= 8.5 Hz, 2H), 7.19 (d, J= 8.5 Hz, 2H), 7.16 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.5 Hz, 2H), 6.41 (t, J= 2.5 Hz, 1H), 4.35-4.32 (m, 2H), 4.22-4.19 (m, 1H), 3.80 (s, 6H), 3.67-3.60 (m, 1H), 3.59-3.55 (m, 1H), 2.90 (dd, J = 4.5, 17.5 Hz, 1H), 2.79 (dd, J = 4.0, 17.0 Hz, 1H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 171.80, 168.41, 161.14, 153.69, 150.50, 139.18, 135.50, 128.97, 127.42, 127.19, 120.99, 104.22, 99.59, 66.65, 54.39, 49.90, 38.29, 34.82; Mass found [M - HCl + H]+ = 459.2; [M - HCl + Na]+ = 481.1; [2M - 2HCl + H]+ = 916.4。 Yield: 68%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.59 (d, J= 8.5Hz, 2H), 7.19 (d, J= 8.5Hz, 2H), 7.16 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.5Hz, 2H), 6.41 (t, J= 2.5Hz, 1H), 4.35-4.32 (m, 2H), 4.22-4.19 (m, 1H), 3.80 (s, 6H), 3.67-3.60 (m, 1H), 3.59-3.55 (m, 1H), 2.90 (dd, J = 4.5, 17.5 Hz, 1H), 2.79 (dd, J = 4.0, 17.0 Hz, 1H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 171.80, 168.41, 161.14, 153.69, 150.50, 139.18, 135.50, 128.97, 127.42, 127.19, 120.99, 104.22, 99.59, 66.65, 54.39, 49.90, 38.29, 34.82; Mass found [M - HCl + H] + = 459.2; [M - HCl + Na] + = 481.1; [2M - 2HCl + H] + = 916.4.

（Ｅ）－２－（２，５－ジアミノ－５－オキソペンタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｑ）
５ｉと同様の合成手順で４ｑから５ｑを得た。 (E)-2-(2,5-diamino-5-oxopentanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5q)
5q was obtained from 4q via a similar synthetic procedure to 5i.

収率６２％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (s, 2H), 6.40 (s, 1H), 4.41-4.35 (m, 1H), 4.34-4.30 (m, 1H), 3.97 (t, J = 6.5 Hz, 1H), 3.80 (s, 6H), 3.72-3.68 (m, 1H), 3.58-3.53 (m, 1H), 2.50-2.47 (m, 2H), 2.16-2.09 (m, 2H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 175.66, 168.78, 161.14, 153.64, 150.50, 139.20, 135.50, 128.97, 127.45, 127.19, 121.00, 104.23, 99.64, 66.66, 54.40, 52.65, 38.21, 30.19, 26.78; Mass found [M - HCl + H]+ = 473.3; [M - HCl + Na]+= 495.3; [2M - 2HCl + H]+ = 944.6。 Yield: 62%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 8.5Hz, 2H), 7.18 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (s, 2H), 6.40 (s, 1H), 4.41-4.35 (m, 1H), 4.34-4.30 (m, 1H), 3.97 (t, J = 6.5Hz, 1H), 3.80 (s, 6H), 3.72-3.68 (m, 1H), 3.58-3.53 (m, 1H), 2.50-2.47 (m, 2H), 2.16-2.09 (m, 2H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 175.66, 168.78, 161.14, 153.64, 150.50, 139.20, 135.50, 128.97, 127.45, 127.19, 121.00, 104.23, 99.64, 66.66, 54.40, 52.65, 38.21, 30.19, 26.78; Mass found [M - HCl + H] + = 473.3; [M - HCl + Na] + = 495.3; [2M - 2HCl + H] + = 944.6.

（Ｅ）－３－アミノ－４－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－４－オキソブタン酸塩酸塩（５ｒ）
５ａの合成手順と同様の方法で４ｒから５ｒを得た。 (E)-3-Amino-4-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-oxobutanoic acid hydrochloride (5r)
5r was obtained from 4r in a similar manner to the synthesis of 5a.

収率８２％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.59 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.37-4.32 (m, 2H), 4.22-4.19 (m, 1H), 3.80 (s, 6H), 3.69-3.64 (m, 1H), 3.58-3.54 (m, 1H), 2.99 (dd, J = 4.0, 18.0 Hz, 1H), 2.89 (dd, J = 4.0, 18.0 Hz, 1H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 171.18, 168.13, 161.14, 153.67, 150.52, 139.19, 135.48, 128.96, 127.44, 127.18, 120.99, 104.23, 99.60, 66.54, 54.39, 49.63, 38.35, 34.60; Mass found [M - HCl + H]+ = 459.1; [2M - 2HCl + H]+ = 917.2。 Yield: 82%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.59 (d, J= 8.5Hz, 2H), 7.18 (d, J= 8.5Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.07 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.37-4.32 (m, 2H), 4.22-4.19 (m, 1H), 3.80 (s, 6H), 3.69-3.64 (m, 1H), 3.58-3.54 (m, 1H), 2.99 (dd, J = 4.0, 18.0 Hz, 1H), 2.89 (dd, J = 4.0, 18.0 Hz, 1H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 171.18, 168.13, 161.14, 153.67, 150.52, 139.19, 135.48, 128.96, 127.44, 127.18, 120.99, 104.23, 99.60, 66.54, 54.39, 49.63, 38.35, 34.60; Mass found [M - HCl + H] + = 459.1; [2M - 2HCl + H] + = 917.2.

（Ｅ）－４－アミノ－５－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－５－オキソペンタン酸塩酸塩（５ｓ）
５ａと同様の合成手順で４ｓから５ｓを得た。 (E)-4-Amino-5-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-5-oxopentanoic acid hydrochloride (5s)
5s was obtained from 4s via a similar synthetic procedure to 5a.

収率８８％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 4.41-4.36 (m, 1H), 4.33-4.29 (m, 1H), 3.96 (t, J =
6.5 Hz, 1H), 3.80 (s, 6H), 3.75-3.70 (m, 1H), 3.55-3.50 (m, 1H), 2.52 (t, J = 7.5 Hz, 2H), 2.18-2.13 (m, 2H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 174.27, 168.72,
161.12, 153.64, 150.51, 139.21, 135.45, 128.93, 127.47, 127.18, 121.00, 104.23,
99.60, 66.61, 54.43, 52.44, 38.15, 28.69, 26.30; Mass found [M - HCl + H]+= 473.0。 Yield 88%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 8.5Hz, 2H), 7.18 (d, J= 8.5Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.07 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (s, 1H), 4.41-4.36 (m, 1H), 4.33-4.29 (m, 1H), 3.96 (t, J =
6.5 Hz, 1H), 3.80 (s, 6H), 3.75-3.70 (m, 1H), 3.55-3.50 (m, 1H), 2.52 (t, J = 7.5 Hz, 2H), 2.18-2.13 (m, 2H); 13C -NMR ( CD3OD , 125 MHz), δ(ppm): 174.27, 168.72,
161.12, 153.64, 150.51, 139.21, 135.45, 128.93, 127.47, 127.18, 121.00, 104.23,
99.60, 66.61, 54.43, 52.44, 38.15, 28.69, 26.30; Mass found [M - HCl + H] + = 473.0.

１－２－２．目的化合物５ｔの合成
スキーム１と同様のスキーム２に従って化合物５ｔを合成した。 1-2-2. Synthesis of target compound 5t Compound 5t was synthesized according to Scheme 2, which is similar to Scheme 1.

スキーム２：化合物５ｔの合成 Scheme 2: Synthesis of compound 5t

試薬および条件：（ａ）ＨＡＴＵ，ＤＩＰＥＡ，ＣＨ２Ｃｌ２，４１％；（ｂ）ＮＥｔ３，ＣＨ２Ｃｌ２，０℃；（ｃ）ＤＭＡＰ，ＡＣＮ，５０℃，５７％；（ｄ）１，４－ジオキサン中４Ｍ ＨＣｌ，ＣＨ２Ｃｌ２，９２％。 Reagents and conditions: (a) HATU, DIPEA, CH 2 Cl 2 , 41%; (b) NEt 3 , CH 2 Cl 2 , 0° C.; (c) DMAP, ACN, 50° C., 57%; (d) 4M HCl in 1,4-dioxane, CH 2 Cl 2 , 92%.

（Ｅ）－４－（３，５－ジメトキシスチリル）フェニル（２－（ピロリジン－２－カルボキサミド）エチル）カーボネート塩酸塩（５ｔ）
５ａと同様の合成手順で１ｔから５ｔの化合物を得た。 (E)-4-(3,5-dimethoxystyryl)phenyl(2-(pyrrolidine-2-carboxamido)ethyl)carbonate hydrochloride (5t)
Compounds 1t to 5t were obtained by the same synthetic procedure as for 5a.

白色粉末。収率９２％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 4.39-4.32 (m, 2H), 4.31-4.27 (m, 1H), 3.80 (s, 6H), 3.69-3.61 (m, 1H), 3.59-3.54 (m, 1H), 3.43-3.36 (m, 1H), 3.34-3.31 (m, 1H), 2.46-2.40 (m, 1H), 2.08-2.01 (m, 3H); 13C-NMR (CD3OD, 125 MHz)
, δ(ppm): 168.66, 161.15, 153.67, 150.52, 139.18, 135.50, 128.98, 127.41, 127.18, 120.95, 104.23, 99.61, 66.62, 59.77, 54.39, 45.95, 38.46, 29.56, 23.59; Mass found [M - HCl + H]+ = 442.0; [M - HCl + Na]+= 464.1; [2M - 2HCl + H]+ = 882.4; [2M - 2HCl + Na]+ = 904.4。 White powder. Yield 92%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.07 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 4.39-4.32 (m, 2H), 4.31-4.27 (m, 1H), 3.80 (s, 6H), 3.69-3.61 (m, 1H), 3.59-3.54 (m, 1H), 3.43-3.36 (m, 1H), 3.34-3.31 (m, 1H), 2.46-2.40 (m, 1H), 2.08-2.01 (m, 3H); 13C -NMR ( CD3OD , 125MHz)
, δ(ppm): 168.66, 161.15, 153.67, 150.52, 139.18, 135.50, 128.98, 127.41, 127.18, 120.95, 104.23, 99.61, 66.62, 59.77, 54.39, 45.95, 38.46, 29.56, 23.59; Mass found [M - HCl + H] + = 442.0; [M - HCl + Na] + = 464.1; [2M - 2HCl + H] + = 882.4; [2M - 2HCl + Na] + = 904.4.

１－２－３．目的化合物５ｕの合成
スキーム１と同様のスキーム３に従って、化合物５ｕを合成した。 1-2-3. Synthesis of target compound 5u Compound 5u was synthesized according to Scheme 3, which is similar to Scheme 1.

スキーム３：化合物５ｕの合成 Scheme 3: Synthesis of compound 5u

試薬および条件：（ａ）ＥＤＣＩ，ＤＩＰＥＡ，ＣＨ２Ｃｌ２，４５％；（ｂ）ＮＥｔ３，ＣＨ２Ｃｌ２，０℃；（ｃ）ＤＭＡＰ，ＡＣＮ，５０℃，３３％；（ｄ）ジオキサン中４Ｍ ＨＣｌ，ＣＨ２Ｃｌ２，９０％。 Reagents and conditions: (a) EDCI, DIPEA, CH2Cl2 , 45%; (b) NEt3 , CH2Cl2 , 0°C; (c) DMAP, ACN, 50°C, 33%; (d) 4M HCl in dioxane, CH2Cl2 , 90%.

（Ｅ）－３－（２－アミノ－３－メチルブタンアミド）プロピル（４－（３，５－ジメトキシスチリル）フェニル）カーボネート塩酸塩（５ｕ）
５ａと同様の合成手順で１ｃおよび３－アミノプロパン－１－オールから化合物５ｕを得た。 (E)-3-(2-amino-3-methylbutanamido)propyl(4-(3,5-dimethoxystyryl)phenyl)carbonate hydrochloride (5u)
Compound 5u was obtained from 1c and 3-aminopropan-1-ol via a similar synthetic procedure to 5a.

白色粉末。収率９０％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.57 (d, J= 8.5 Hz, 2H), 7.16 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.06 (d, J= 16.5 Hz, 1H), 6.70 (d, J= 1.5 Hz, 2H), 6.40 (s, 1H), 4.30 (t, J = 6.5 Hz, 2H), 3.80 (s, 6H), 3.65 (d, J = 5.5 Hz, 1H), 3.47-3.41 (m, 1H), 3.39-3.34 (m, 1H), 2.21-2.17 (m, 1H), 2.00-1.95 (m, 3H), 1.06 (t, J = 7.5 Hz, 6H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.22, 161.12, 153.66, 150.56, 139.21, 135.40, 128.91, 127.46, 127.18, 120.97
, 104.23, 99.61, 65.92, 58.54, 54.40, 35.77, 30.05, 28.09, 17.51, 16.62; Mass found [M - HCl + H]+ = 457.3; [M - HCl + Na]+ = 479.2; [2M - 2HCl + Na]+ = 935.4。 White powder. Yield: 90%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.57 (d, J= 8.5Hz, 2H), 7.16 (d, J= 8.5Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.06 (d, J= 16.5Hz, 1H), 6.70 (d, J= 1.5Hz, 2H), 6.40 (s, 1H), 4.30 (t, J = 6.5Hz, 2H), 3.80 (s, 6H), 3.65 (d, J = 5.5Hz, 1H), 3.47-3.41 (m, 1H), 3.39-3.34 (m, 1H), 2.21-2.17 (m, 1H), 2.00-1.95 (m, 3H), 1.06 (t, J = 7.5 Hz, 6H); 13C -NMR ( CD3OD , 125 MHz), δ(ppm): 168.22, 161.12, 153.66, 150.56, 139.21, 135.40, 128.91, 127.46, 127.18, 120.97
, 104.23, 99.61, 65.92, 58.54, 54.40, 35.77, 30.05, 28.09, 17.51, 16.62; Mass found [M - HCl + H] + = 457.3; [M - HCl + Na] + = 479.2; [2M - 2HCl + Na] + = 935.4.

１－２－４．目的化合物５ｖおよび５ｗの合成
スキーム４に示すように、化合物５ａまたは化合物５ｃを炭酸ナトリウムで中和した後、ニコチン酸で処理すると、対応するニコチン酸塩５ｖ、ニコチン酸塩５ｗを得た。 1-2-4. Synthesis of Target Compounds 5v and 5w As shown in Scheme 4, compound 5a or compound 5c was neutralized with sodium carbonate and then treated with nicotinic acid to give the corresponding nicotinate salts 5v and 5w.

スキーム４：化合物５ｖおよび５ｗの合成 Scheme 4: Synthesis of compounds 5v and 5w

試薬および条件：（ａ）１．Ｋ２ＣＯ３，Ｈ２Ｏ，ＣＨ２Ｃｌ２，１時間；２．ニコチン酸，エタノール，３時間。 Reagents and conditions: (a) 1. K2CO3 , H2O , CH2Cl2 , 1 hr; 2. Nicotinic acid, ethanol, 3 hr.

（Ｅ）－２－（２－アミノアセトアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネートニコチネート（５ｖ）
ＣＨ２Ｃｌ２（２０ｍＬ）中の化合物５ａ（０．４２ｇ，１．０ｍｍｏｌ）の撹拌溶液に、Ｈ２Ｏ（０．４ｍＬ）中のＫ２ＣＯ３（０．１８２ｇ，１．３ｍｍｏｌ）を加え、反応混合物を室温で１時間撹拌した。溶媒を真空下で除去して遊離アミンを得て、これを１０ｍＬのエタノールに溶解し、ニコチン酸（０．１４５ｇ，１．２ｍｍｏｌ）を添加した。反応混合物を室温で３時間撹拌した。溶媒を蒸発させ、粗生成物をエタノールおよび脱水エーテルから再結晶して、化合物５ｖを白色粉末として得た（０．３９ｇ，収率７８％）。1H-NMR (CDCl3, 500 MHz), δ(ppm): 9.07 (s, 1H), 8.57-8.56 (m, 1H), 8.34 (t, J = 2.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.47-7.44 (m, 1H), 7.18-7.14 (m, 3H),
7.08 (d, J = 16.5 Hz, 1H), 6.72 (d, J = 2.5 Hz, 2H), 6.41 (t, J = 2.5 Hz, 1H), 4.33 (t, J = 5.0 Hz, 2H), 3.81 (s, 6H), 3.68-3.66 (m, 2H), 3.61 (t, J = 5.0 Hz, 2H)。 (E)-2-(2-aminoacetamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate nicotinate (5v)
To a stirred solution of compound 5a (0.42 g, 1.0 mmol) in CH 2 Cl 2 (20 mL), K 2 CO 3 (0.182 g, 1.3 mmol) in H 2 O (0.4 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum to give the free amine, which was dissolved in 10 mL of ethanol, and nicotinic acid (0.145 g, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated, and the crude product was recrystallized from ethanol and anhydrous ether to give compound 5v as a white powder (0.39 g, 78% yield). 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 9.07 (s, 1H), 8.57-8.56 (m, 1H), 8.34 (t, J = 2.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.47-7.44 (m, 1H), 7.18-7.14 (m, 3H),
7.08 (d, J = 16.5 Hz, 1H), 6.72 (d, J = 2.5 Hz, 2H), 6.41 (t, J = 2.5 Hz, 1H), 4.33 (t, J = 5.0 Hz, 2H), 3.81 (s, 6H), 3.68-3.66 (m, 2H), 3.61 (t, J = 5.0 Hz, 2H).

（Ｅ）－２－（２－アミノ－３－メチルブタンアミド）エチル（４－（３，５－ジメトキシスチリル）フェニル）カーボネートニコチネート（５ｗ）
５ｖと同様の合成手順で５ｃから５ｗを得た。 (E)-2-(2-amino-3-methylbutanamido)ethyl(4-(3,5-dimethoxystyryl)phenyl)carbonate nicotinate (5w)
5w was obtained from 5c via a similar synthetic procedure to 5v.

白色粉末。収率７９％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 9.19 (s, 1H), 8.70 (d,
J = 3.5 Hz, 1H), 8.32-8.30 (m, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.40-7.37 (m, 1H), 7.13 (d, J= 8.5 Hz, 2H), 7.03 (d, J= 16.5 Hz, 1H), 6.96 (d, J= 16.5 Hz, 1H), 6.63 (d, J= 2.5 Hz, 2H), 6.38 (t, J= 2.5 Hz, 1H), 4.33-4.28 (m, 2H), 3.80 (s, 6H), 3.67-3.62 (m, 2H), 3.56-3.53 (m, 1H), 2.20-2.05 (m, 1H), 1.02-0.90 (m, 6H)。 White powder. Yield: 79%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 9.19 (s, 1H), 8.70 (d,
J = 3.5 Hz, 1H), 8.32-8.30 (m, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.40-7.37 (m, 1H), 7.13 (d, J= 8.5 Hz, 2H), 7.03 (d, J= 16.5 Hz, 1H), 6.96 (d, J= 16.5 Hz, 1H), 6.63 (d, J= 2.5 Hz, 2H), 6.38 (t, J= 2.5 Hz, 1H), 4.33- 4.28 (m, 2H), 3.80 (s, 6H), 3.67-3.62 (m, 2H), 3.56-3.53 (m, 1H), 2.20-2.05 (m, 1H), 1.02-0.90 (m, 6H).

１－２－５．目的化合物６ａ～６ｈの合成
スキーム５に従って、化合物６ａ～６ｈを合成した。示されるように、出発物質４－ヒドロキシベンズアルデヒド（１１ａ～１１ｂ）をイミダゾールおよびＴＩＰＳで処理して対応するシリルエーテル（１２ａ～１２ｂ）を形成し、これをＮａＢＨ４で還元して対応
するカルビノール（１３ａ～１３ｂ）を得た。化合物１３ａ～１３ｂを亜リン酸トリエチルおよびＺｎＩ２で処理し、対応するホスホン酸塩（１４ａ～１４ｂ）を得た。化合物１４ａ～１４ｂをそれぞれ市販のアルデヒド（１５ａ～１５ｄ）とカップリングさせて対応する１６ａ～１６ｄを得て、その後ＴＨＦ中のＢｕ４ＮＦで処理して目的の化合物１７ａ～１７ｄを得た。一方、化合物２ａ、２ｃおよび２ｊをｐ－ニトロフェニルクロロホルメートと反応させて対応する１８ａ、１８ｃおよび１８ｊを得て、これをさらなる精製をせずにＤＭＡＰの存在下で１７ａ～１７ｄと別々に反応させて、対応する炭酸塩１９ａ～１９ｈを得た。その後、１９ａ～１９ｈを１，４－ジオキサン中４Ｍ ＨＣｌで脱保護し、目的化合物６ａ～６ｈを得た。 1-2-5. Synthesis of target compounds 6a-6h Compounds 6a-6h were synthesized according to Scheme 5. As shown, starting material 4-hydroxybenzaldehyde (11a-11b) was treated with imidazole and TIPS to form the corresponding silyl ether (12a-12b), which was reduced with NaBH4 to give the corresponding carbinol (13a-13b). Compounds 13a-13b were treated with triethyl phosphite and ZnI2 to give the corresponding phosphonate (14a-14b). Compounds 14a-14b were coupled with commercially available aldehydes (15a-15d), respectively, to give the corresponding 16a-16d, which were then treated with Bu4NF in THF to give the target compounds 17a-17d. Meanwhile, compounds 2a, 2c and 2j were reacted with p-nitrophenyl chloroformate to give the corresponding 18a, 18c and 18j, which were reacted separately with 17a-17d in the presence of DMAP without further purification to give the corresponding carbonates 19a-19h, which were then deprotected with 4 M HCl in 1,4-dioxane to give the target compounds 6a-6h.

スキーム５：化合物６ａ～６ｈの合成 Scheme 5: Synthesis of compounds 6a-6h

試薬および条件：(a)イミダゾール，ＴＩＰＳＣｌ，ＣＨ２Ｃｌ２，１６時間；（ｂ）
ＮａＢＨ４，ＴＨＦ，ＭｅＯＨ，０℃，１時間；（ｃ）ＺｎＩ２，亜リン酸トリエチル，ＴＨＦ，８０℃，１６ｈ；（ｄ）ｔ－ＢｕＯＫ，ＴＨＦ，０℃，３ｈ；（ｅ）ＴＨＦ中１
．０Ｍ Ｂｕ４ＮＦ，ＴＨＦ；（ｆ）ＮＥｔ３，ＣＨ２Ｃｌ２，０℃；（ｇ）ＤＭＡＰ，ＡＣＮ，５０℃；（ｈ）１，４－ジオキサン，ＣＨ２Ｃｌ２中４Ｍ ＨＣｌ，ＣＨ２Ｃｌ２。 Reagents and conditions: (a) Imidazole, TIPSCl, CH2Cl2 , 16 hours; (b)
(c) ZnI 2 , triethyl phosphite, THF, 80° C., 16 h; (d) t-BuOK, THF, 0° C., 3 h ; (e) 1 in THF
0M Bu 4 NF, THF; (f) NEt 3 , CH 2 Cl 2 , 0° C.; (g) DMAP, ACN, 50° C.; (h) 1,4-dioxane, 4M HCl in CH 2 Cl 2 , CH 2 Cl 2 .

４－（（トリイソプロピルシリル）オキシ）ベンズアルデヒド（１２ａ）
ＤＣＭ（５００ｍＬ）中の４－ヒドロキシベンズアルデヒド１１ａ（５０ｇ，４０９．８ｍｍｏｌ）の溶液に、イミダゾール（４１．８ｇ，６１４．７ｍｍｏｌ）を加え、その後、ＴＩＰＳＣｌ（８６．５ｇ，４５０．８ｍｍｏｌ）を滴下して加えた。混合物を１６時間撹拌し、氷／水に注ぎ、ＤＣＭで抽出した。有機層をブラインで洗浄し，Ｎａ２ＳＯ４で乾燥させ，蒸発させた。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／石油エーテル＝１／５０）で精製し、化合物１２ａ（９５ｇ、９９％）を黄色オイルとして得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 9.88 (s, 1H, CHO), 7.78 (dd,
J = 2.0, 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 1.32-1.25 (m, 3H), 1.11 (d, J= 8.0 Hz, 18H)。 4-((triisopropylsilyl)oxy)benzaldehyde (12a)
To a solution of 4-hydroxybenzaldehyde 11a (50 g, 409.8 mmol) in DCM (500 mL) was added imidazole (41.8 g, 614.7 mmol) followed by dropwise addition of TIPSCl (86.5 g, 450.8 mmol). The mixture was stirred for 16 h, poured into ice/water and extracted with DCM. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/petroleum ether=1/50) to give compound 12a (95 g, 99%) as a yellow oil. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 9.88 (s, 1H, CHO), 7.78 (dd,
J = 2.0, 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 1.32-1.25 (m, 3H), 1.11 (d, J= 8.0 Hz, 18H).

３－メトキシ－４－（（トリイソプロピルシリル）オキシ）ベンズアルデヒド（１２ｂ）
１２ａと同様の合成手順で１１ｂから１２ｂを得た。 3-Methoxy-4-((triisopropylsilyl)oxy)benzaldehyde (12b)
12b was obtained from 11b via a similar synthetic procedure to 12a.

黄色オイル。収率９８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 9.83 (s, 1H, CHO), 7.39 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 1.5, 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 1.31-1.25 (m, 3H), 1.09 (d, J = 7.5 Hz, 18H)。 Yellow oil. Yield: 98%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 9.83 (s, 1H, CHO), 7.39 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 1.5, 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 1.31-1.25 (m, 3H), 1.09 (d, J = 7.5 Hz, 18H).

（４－（（トリイソプロピルシリル）オキシ）フェニル）メタノール（１３ａ）
ＭｅＯＨ／ＴＨＦ（１：１，１Ｌ）中の化合物１２ａ（１００ｇ，３５９．７ｍｍｏｌ）の溶液に、０℃でＮａＢＨ４（２７．３ｇ，７１９．４ｍｍｏｌ）を加え、１時間撹拌した。反応混合物を氷／水に注ぎ、ＤＣＭで抽出した。有機層をブラインで洗浄し，Ｎａ２ＳＯ４で乾燥させ，蒸発させた。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／石油エーテル＝１／２０）で精製し、化合物１３ａ（８８ｇ、収率９９％）を黄色オイルとして得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.21 (d, J= 8.5 Hz, 2H), 6.86 (d, J= 8.5 Hz, 2H), 4.60 (d, J= 5.0 Hz, 2H), 1.29-1.22 (m, 3H), 1.10-1.06 (m, 18H)。 (4-((triisopropylsilyl)oxy)phenyl)methanol (13a)
To a solution of compound 12a (100 g, 359.7 mmol) in MeOH/THF (1:1, 1 L) was added NaBH 4 (27.3 g, 719.4 mmol) at 0° C. and stirred for 1 h. The reaction mixture was poured into ice/water and extracted with DCM. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/petroleum ether=1/20) to give compound 13a (88 g, 99% yield) as a yellow oil. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.21 (d, J= 8.5 Hz, 2H), 6.86 (d, J= 8.5 Hz, 2H), 4.60 (d, J= 5.0 Hz, 2H), 1.29-1.22 (m, 3H), 1.10-1.06 (m, 18H).

（３－メトキシ－４－（（トリイソプロピルシリル）オキシ）フェニル）メタノール（１３ｂ）
１３ａと同様の合成手順で１２ｂから１３ｂを得た。 (3-Methoxy-4-((triisopropylsilyl)oxy)phenyl)methanol (13b)
13b was obtained from 12b via a similar synthetic procedure to 13a.

黄色オイル。収率９５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 6.89 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 3.81 (s, 3H), 1.57 (s, 1H), 1.28-1.22 (m, 3H), 1.09 (d, J = 7.5 Hz, 18H)。 Yellow oil. Yield: 95%. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 6.89 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 3.81 (s, 3H), 1.57 (s, 1H), 1.28-1.22 (m, 3H), 1.09 (d, J = 7.5 Hz, 18H).

ジエチル（４－（（トリイソプロピルシリル）オキシ）ベンジル）ホスホネート（１４ａ）
ＴＨＦ（８５０ｍＬ）中の化合物１３ａ（８５ｇ，３０３．６ｍｍｏｌ）の溶液に、ＺｎＩ２（１４５．３ｇ，４５５．４ｍｍｏｌ）および亜リン酸トリエチル（１００．８ｇ，６０７．２ｍｍｏｌ）を添加した。混合物を１６時間還流させ、蒸発させた。残渣に２Ｎ ＮａＯＨ（５００ｍＬ）を加え、エーテルで抽出した。有機層をブラインで洗浄し，Ｎａ２ＳＯ４で乾燥させ，蒸発させた。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／石油エーテル＝１／３０）で精製し、化合物１４ａ（９０ｇ、収率７５％）を黄色オイルとして得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.16 (dd, J= 2
.5, 8.5 Hz, 2H), 6.81 (d, J= 8.5 Hz, 2H), 4.07-4.03 (m, 4H), 3.20 (d, J = 21.0 Hz, 2H), 1.65-1.21 (m, 9H), 1.08 (d, J = 7.0 Hz, 18H)。 Diethyl (4-((triisopropylsilyl)oxy)benzyl)phosphonate (14a)
To a solution of compound 13a (85 g, 303.6 mmol) in THF (850 mL) was added ZnI 2 (145.3 g, 455.4 mmol) and triethyl phosphite (100.8 g, 607.2 mmol). The mixture was refluxed for 16 h and evaporated. The residue was added with 2N NaOH (500 mL) and extracted with ether. The organic layer was washed with brine, dried over Na 2 SO 4 , and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/petroleum ether=1/30) to give compound 14a (90 g, 75% yield) as a yellow oil. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 7.16 (dd, J= 2
.5, 8.5 Hz, 2H), 6.81 (d, J= 8.5 Hz, 2H), 4.07-4.03 (m, 4H), 3.20 (d, J = 21.0 Hz, 2H), 1.65-1.21 (m, 9H), 1.08 (d, J = 7.0 Hz, 18H).

ジエチル（３－メトキシ－４－（（トリイソプロピルシリル）オキシ）ベンジル）ホスホネート（１４ｂ）
１４ａと同様の合成手順で１３ｂから１４ｂを得た。 Diethyl (3-methoxy-4-((triisopropylsilyl)oxy)benzyl)phosphonate (14b)
14b was obtained from 13b via a similar synthetic procedure to 14a.

黄色オイル。収率７８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 6.83-6.79 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 4.17-3.90 (m, 4H), 3.79 (s, 3H), 3.07 (d, J = 21.0 Hz, 2H), 1.38-1.19 (m, 9H), 1.08-1.03 (m, 18H)。 Yellow oil. Yield 78%. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 6.83-6.79 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 4.17-3.90 (m, 4H), 3.79 (s, 3H), 3.07 (d, J = 21.0 Hz, 2H), 1.38-1.19 (m, 9H), 1.08-1.03 (m, 18H).

（Ｅ）－（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）トリイソプロピルシラン（１６ａ）
ＴＨＦ（１７５ｍＬ）中の化合物１４ａ（７．０ｇ，１７．５ｍｍｏｌ）の溶液に、０℃で化合物１５ａ（３．０ｇ，１７．５ｍｍｏｌ）およびｔ－ＢｕＯＫ（４．１ｇ，３６．７ｍｍｏｌ）を加え、０℃で３時間撹拌した。反応混合物を氷／水に注ぎ、ＥＡで抽出した。有機層をブラインで洗浄し，Ｎａ２ＳＯ４で乾燥させ，蒸発させた。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／８）で精製し、化合物１６ａ（５．６ｇ、収率７６％）を白色固体として得た。1H-NMR (CDCl3, 500
MHz), δ(ppm): 7.37 (d, J= 8.0 Hz, 2H), 7.03 (d, J= 16.5 Hz, 1H), 6.91-6.86 (m,
3H), 6.65 (s, 2H), 6.37 (d, J = 2.0 Hz, 1H), 1.29-1.24 (m, 3H), 1.12 (d, J= 7.5
Hz, 18 H)。 (E)-(4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)triisopropylsilane (16a)
To a solution of compound 14a (7.0 g, 17.5 mmol) in THF (175 mL) was added compound 15a (3.0 g, 17.5 mmol) and t-BuOK (4.1 g, 36.7 mmol) at 0° C. and stirred at 0° C. for 3 h. The reaction mixture was poured into ice/water and extracted with EA. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/n-hexane=1/8) to give compound 16a (5.6 g, 76% yield) as a white solid. 1 H-NMR (CDCl 3 , 500
MHz), δ(ppm): 7.37 (d, J= 8.0 Hz, 2H), 7.03 (d, J= 16.5 Hz, 1H), 6.91-6.86 (m,
3H), 6.65 (s, 2H), 6.37 (d, J = 2.0 Hz, 1H), 1.29-1.24 (m, 3H), 1.12 (d, J= 7.5
Hz, 18 H).

（Ｅ）－（４－（３，５－ジエトキシスチリル）フェノキシ）トリイソプロピルシラン（１６ｂ）
１６ａと同様の合成手順で１４ｂおよび１５ｂから１６ｂを得た。 (E)-(4-(3,5-diethoxystyryl)phenoxy)triisopropylsilane (16b)
Following a similar synthetic procedure to 16a, 16b was obtained from 14b and 15b.

白色粉末。収率７５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.36 (d, J= 8.5 Hz, 2H), 7.01 (d, J= 16.0 Hz, 1H), 6.88 (d, J= 16.0 Hz, 1H), 6.87 (d, J= 8.5 Hz, 2H), 6.63 (d, J= 2.0 Hz, 2H), 6.37 (t, J= 2.0 Hz, 1H), 4.05 (q, J= 7.0 Hz, 4H), 1.43 (t, J= 7.0 Hz, 6H), 1.29-1.25 (m, 3H), 1.11 (d, J = 7.5 Hz, 18H)。 White powder. Yield 75%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.36 (d, J= 8.5 Hz, 2H), 7.01 (d, J= 16.0 Hz, 1H), 6.88 (d, J= 16.0 Hz, 1H), 6.87 (d, J= 8.5 Hz, 2H), 6.63 (d, J= 2.0 Hz, 2H), 6.37 (t, J= 2.0 Hz, 1H), 4.05 (q, J= 7.0 Hz, 4H), 1.43 (t, J= 7.0 Hz, 6H), 1.29-1.25 (m, 3H), 1.11 (d, J = 7.5 Hz, 18H).

（Ｅ）－（４－（３，５－ジメトキシスチリル）－２－メトキシフェノキシ）トリイソプロピルシラン（１６ｃ）
１６ａと同様の合成手順で１４ｃおよび１５ｃから１６ｃを得た。 (E)-(4-(3,5-dimethoxystyryl)-2-methoxyphenoxy)triisopropylsilane (16c)
Following a similar synthetic procedure to 16a, 16c was obtained from 14c and 15c.

白色固体。収率７８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.03-7.00 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.88-6.85 (m, 1H), 6.65 (s, 2H), 6.38 (s, 1H), 3.87 (s, 3H), 3.83 (s, 6H), 1.30-1.23 (m, 3H), 1.11 (d, J = 7.5 Hz, 18H)。 White solid. Yield: 78%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.03-7.00 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.88-6.85 (m , 1H), 6.65 (s, 2H), 6.38 (s, 1H), 3.87 (s, 3H), 3.83 (s, 6H), 1.30-1.23 (m, 3H), 1.11 (d, J = 7.5 Hz, 18H).

（Ｅ）－（４－（３，５－ジメトキシスチリル）－２－メトキシフェノキシ）トリイソプロピルシラン（１６ｄ）
１６ａと同様の合成手順で１４ｄおよび１５ｄから１６ｄを得た。 (E)-(4-(3,5-dimethoxystyryl)-2-methoxyphenoxy)triisopropylsilane (16d)
Following a similar synthetic procedure to 16a, 16d was obtained from 14d and 15d.

淡黄色固体。収率７７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.30 (d, J= 9.0 Hz, 2H), 6.91 (dd, J= 10.5, 16.5 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.81 (dd, J = 10.5, 16.5 Hz, 1H), 6.62 (d, J = 16.5 Hz, 1H), 6.59 (d, J = 2.0 Hz, 2H), 6.55 (d, J = 16.5 Hz, 1H), 6.36 (t, J= 2.0 Hz, 1H), 3.81 (s, 6H), 1.30-1.22 (m, 3H), 1.11
(d, J = 7.5 Hz, 18H)。 Pale yellow solid. Yield 77%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.30 (d, J= 9.0 Hz, 2H), 6.91 (dd, J= 10.5, 16.5 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.81 (dd, J = 10.5, 16.5 Hz, 1H), 6.62 (d, J = 16.5 Hz, 1H), 6.59 (d, J = 2.0 Hz, 2H), 6.55 (d, J = 16.5 Hz, 1H), 6.36 (t, J= 2.0 Hz, 1H), 3.81 (s, 6H), 1.30-1.22 (m, 3H), 1.11
(d, J = 7.5 Hz, 18H).

（Ｅ）－４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノール（１７ａ）
脱水ＴＨＦ（１５ｍＬ）中の化合物１６ａ（０．８０ｇ，１．９ｍｍｏｌ）の溶液と、テトラブチルアンモニウムフロライド（ＴＨＦ中１．０Ｍ，２．５０ｍＬ，２．５ｍｍｏｌ）とをＮ２雰囲気下で室温で２時間撹拌した。反応混合物をＥｔＯＡｃで希釈し、有機層を水で洗浄した。有機層をＮａ２ＳＯ４上で乾燥させて蒸発させ、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ－ヘキサン＝１／８）で精製して、生成物１７ａ（０．４６ｇ，収率９１％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.39 (d, J= 8.5 Hz, 2H), 7.03 (d, J= 16.5 Hz, 1H), 6.92-6.82 (m, 3H), 6.65 (d, J = 2.5 Hz, 2H), 6.38 (t, J = 2.5 Hz, 1H)。 (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenol (17a)
A solution of compound 16a (0.80 g, 1.9 mmol) in dry THF (15 mL) and tetrabutylammonium fluoride (1.0 M in THF, 2.50 mL, 2.5 mmol) was stirred at room temperature under N2 atmosphere for 2 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water. The organic layer was dried over Na2SO4 and evaporated, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/n-hexane=1/8) to give product 17a (0.46 g, yield 91%) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.39 (d, J= 8.5 Hz, 2H), 7.03 (d, J= 16.5 Hz, 1H), 6.92-6.82 (m, 3H), 6.65 (d, J = 2.5 Hz, 2H), 6.38 (t, J = 2.5 Hz, 1H).

（Ｅ）－４－（３，５－ジエトキシスチリル）フェノール（１７ｂ）
１７ａと同様の合成手順で１６ｂから１７ｂを得た。 (E)-4-(3,5-diethoxystyryl)phenol (17b)
17b was obtained from 16b via a similar synthetic procedure to 17a.

白色粉末。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.38 (d, J= 8.5 Hz, 2H), 7.01 (d, J= 16.0 Hz, 1H), 6.89-6.81 (m, 3H), 6.63 (d, J = 2.5 Hz, 2H), 6.37 (t, J = 2.5 Hz, 1H), 4.08-4.04 (m, 4H), 1.42 (t, J = 7.5 Hz, 6H)。 White powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.38 (d, J= 8.5 Hz, 2H), 7.01 (d, J= 16.0 Hz, 1H), 6.89-6.81 (m, 3H), 6.63 (d, J = 2.5 Hz, 2H), 6.37 (t, J = 2.5 Hz, 1H), 4.08-4.04 (m, 4H), 1.42 (t, J = 7.5 Hz, 6H).

（Ｅ）－４－（３，５－ジメトキシスチリル）－２－メトキシフェノール（１７ｃ）
１７ａと同様の合成手順で１６ｃから１７ｃを得た。 (E)-4-(3,5-dimethoxystyryl)-2-methoxyphenol (17c)
17c was obtained from 16c via a similar synthetic procedure to 17a.

白色粉末。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.04-7.00 (m, 3H), 6.92-6.87 (m, 2H), 6.66 (s, 2H), 6.39 (s, 1H), 5.68 (brs, 1H, OH), 3.96 (s, 3H), 3.83 (s, 6H)。 White powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.04-7.00 (m, 3H), 6.92-6.87 (m, 2H), 6.66 (s, 2H), 6.39 (s, 1H), 5.68 (brs, 1H, OH), 3.96 (s, 3H), 3.83 (s, 6H).

４－（（１Ｅ，３Ｅ）－４－（３，５－ジメトキシフェニル）ブタ－１，３－ジエン－１－イル）フェノール（１７ｄ）
１７ａと同様の合成手順で１６ｄから１７ｄを得た。 4-((1E,3E)-4-(3,5-dimethoxyphenyl)buta-1,3-dien-1-yl)phenol (17d)
17d was obtained from 16d by a similar synthetic procedure to 17a.

白色粉末。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.33 (d, J= 8.0 Hz, 2H), 6.91 (dd,
J= 10.0, 15.5 Hz, 1H), 6.83-6.78 (m, 3H), 6.62 (d, J = 15.5 Hz, 1H), 6.59 (d, J
= 2.0 Hz, 2H), 6.55 (d, J = 15.5 Hz, 1H), 6.37 (t, J = 2.0 Hz, 1H), 4.94 (brs, 1H, OH), 3.82 (s, 6H)。 White powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.33 (d, J= 8.0 Hz, 2H), 6.91 (dd,
J = 10.0, 15.5 Hz, 1H), 6.83-6.78 (m, 3H), 6.62 (d, J = 15.5 Hz, 1H), 6.59 (d, J
= 2.0 Hz, 2H), 6.55 (d, J = 15.5 Hz, 1H), 6.37 (t, J = 2.0 Hz, 1H), 4.94 (brs, 1H, OH), 3.82 (s, 6H).

ｔｅｒｔ－ブチル（Ｅ）－（２－（（２－（（（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）カルボニル）オキシ）エチル）アミノ）－２－オキソエチル）カルバメート（１９ａ）
脱水ＣＨ２Ｃｌ２（１５ｍｌ）中の化合物２ａ（１．１２ｇ，５．１ｍｍｏｌ）の撹拌溶液にトリエチルアミン（２．１５ｍＬ，１５．４ｍｍｏｌ）を加え、次に４－ニトロフェニルクロロホルメート溶液（１．１５ｇ，５．７ｍｍｏｌ、１０ｍＬ ＣＨ２Ｃｌ２中）を０℃で滴下して添加した。反応混合物を０℃で１５分間撹拌し、室温に温めた。混合物を室温でさらに４時間撹拌した。反応終了後（ＴＬＣで確認）、溶媒を蒸発させて除去した。粗中間体をＡＣＮ（３０ｍｌ）中のプテロスチルベン誘導体１７ａ（１．４１ｇ，５．４ｍｍｏｌ）およびＤＭＡＰ（１．２６ｇ，１０．３ｍｍｏｌ）と混合した。得られた混合物を５０℃で１時間加熱した。反応後、溶媒を真空下で除去して粗残渣を得て、これをカラムクロマトグラフィー（ＥＡ／ｎ－ヘキサン＝１／５（Ｖ／Ｖ））で精製して粗生成物を得た。粗生成物を分取ＨＰＬＣ（７０％ＡＣＮ，３０％Ｈ２Ｏ）で精製し、目的化合物１９ａ（０．９９ｇ，収率３８％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5
Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.53 (brs, NH), 6.40 (t, J = 2.0 Hz, 1H), 5.12 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 3.83 (d, J = 5.
5 Hz, 2H), 3.66 (q, J = 5.5 Hz, 2H), 1.46 (s, 9H). Mass found [M - Boc + H]+= 408.3; [M + H]+ = 508.4; [M + Na]+ = 530.4, [2M + H]+= 914.6。 tert-Butyl (E)-(2-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)oxy)ethyl)amino)-2-oxoethyl)carbamate (19a)
To a stirred solution of compound 2a (1.12 g, 5.1 mmol) in dry CH 2 Cl 2 (15 ml) was added triethylamine (2.15 mL, 15.4 mmol), followed by dropwise addition of 4-nitrophenyl chloroformate solution (1.15 g, 5.7 mmol, in 10 mL CH 2 Cl 2 ) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and warmed to room temperature. The mixture was stirred at room temperature for another 4 h. After completion of the reaction (checked by TLC), the solvent was removed by evaporation. The crude intermediate was mixed with pterostilbene derivative 17a (1.41 g, 5.4 mmol) and DMAP (1.26 g, 10.3 mmol) in ACN (30 ml). The resulting mixture was heated at 50° C. for 1 h. After the reaction, the solvent was removed under vacuum to give a crude residue, which was purified by column chromatography (EA/n-hexane=1/5 (V/V)) to give the crude product. The crude product was purified by preparative HPLC (70% ACN, 30% H 2 O) to give the target compound 19a (0.99 g, 38% yield) as a white powder. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5
Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.53 (brs, NH), 6.40 (t, J = 2.0 Hz, 1H), 5.12 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 3.83 (d, J = 5.
5 Hz, 2H), 3.66 (q, J = 5.5 Hz, 2H), 1.46 (s, 9H). Mass found [M - Boc + H] + = 408.3; [M + H] + = 508.4; [M + Na] + = 530.4, [2M + H] + = 914.6.

ｔｅｒｔ－ブチル（Ｅ）－（２－（（２－（（（４－（３，５－ジエトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－２－オキソエチル）カルバメート（１９ｂ）
１９ａと同様の合成手順で２ａおよび１７ｂから１９ｂを得た。 tert-Butyl (E)-(2-((2-(((4-(3,5-diethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-2-oxoethyl)carbamate (19b)
19b was obtained from 2a and 17b via a similar synthetic procedure to 19a.

白色粉末。収率４５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.50 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.97 (d, J= 16.5 Hz, 1H), 6.64 (d, J= 2.0 Hz, 2H), 6.53 (brs, NH), 6.40 (t, J = 2.0 Hz, 1H), 5.12 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 4.06 (q, J = 7.0 Hz, 4H), 3.83 (d, J = 5.5 Hz, 2H),
3.66 (q, J= 5.5 Hz, 2H), 1.46 (s, 9H), 1.43 (t, J = 7.0 Hz, 6H). Mass found [M - Boc + H]+ = 430.3; [M + H]+ = 530.3; [M + Na]+= 552.2, [2M + H]+ = 1058.6, [2M
+ Na]+= 1080.6。 White powder. Yield: 45%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.50 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.97 (d, J= 16.5 Hz, 1H), 6.64 (d, J= 2.0 Hz, 2H), 6.53 (brs, NH), 6.40 (t, J = 2.0 Hz, 1H), 5.12 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 4.06 (q, J = 7.0 Hz, 4H), 3.83 (d, J = 5.5 Hz, 2H),
3.66 (q, J= 5.5 Hz, 2H), 1.46 (s, 9H), 1.43 (t, J = 7.0 Hz, 6H). Mass found [M - Boc + H] + = 430.3; [M + H] + = 530.3; [M + Na] + = 552.2, [2M + H] + = 1058.6, [2M
+ Na] + = 1080.6.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）カルボニル）オキシ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（１９ｃ）
１９ａと同様の合成手順で２ｃおよび１７ａから１９ｃを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19c)
Following a similar synthetic procedure to 19a, 19c was obtained from 2c and 17a.

白色粉末。収率４２％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.18 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 6.39 (brs, NH), 5.03 (brs, NH), 4.34 (t, J = 5.5 Hz, 2H), 3.93-3.91 (m, 1H), 3.70-3.61 (m, 2H), 2.17-2.16 (m, 1H), 1.44 (s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H]+ = 450.2; [M + H]+= 550.4; [M + Na]+ = 572.4。 White powder. Yield 42%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.52 (d, J= 9.0Hz, 2H), 7.18 (d, J= 9.0Hz, 2H), 7.06 (d, J= 16.5Hz, 1H), 6.99 (d, J= 16.5Hz, 1H), 6.66 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 6.39 (brs, NH), 5.03 (brs, NH), 4.34 (t, J = 5.5Hz, 2H), 3.93-3.91 (m, 1H), 3.70-3.61 (m, 2H), 2.17-2.16 (m, 1H), 1.44 (s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H] + = 450.2; [M + H] + = 550.4; [M + Na] + = 572.4.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジエトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（１９ｄ）
１９ａと同様の合成手順で２ｃおよび１７ｂから１９ｄを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-diethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19d)
A similar synthetic procedure to 19a was used to obtain 19d from 2c and 17b.

白色粉末。収率４１％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.50 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.97 (d, J= 16.0 Hz, 1H), 6.64 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 6.38 (brs, NH), 5.03 (brs, NH), 4.34 (t, J = 5.5 Hz, 2H), 4.05 (q, J = 7.0 Hz, 4H), 3.93-3.90 (m, 1H), 3.70-3.61 (m, 2H), 2.19-2.16 (m, 1H), 1.45 (s, 9H), 1.43 (t, J = 7.0 Hz, 6H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J= 7.0 Hz, 3H). Mass found [M - Boc + H]+ = 472.3; [M + H]+ = 572.4; [M + Na]+= 594.4; [2M + H]+ = 1142.8; [2M + Na]+ = 1164.9。 White powder. Yield 41%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.50 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.97 (d, J= 16.0 Hz, 1H), 6.64 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 6.38 (brs, NH), 5.03 (brs, NH), 4.34 (t, J = 5.5 Hz, 2H), 4.05 (q, J = 7.0 Hz, 4H), 3.93-3.90 (m, 1H), 3.70-3.61 (m, 2H), 2.19-2.16 (m, 1H), 1.45 (s, 9H), 1.43 (t, J = 7.0 Hz, 6H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J= 7.0 Hz, 3H). Mass found [M - Boc + H] + = 472.3; [M + H] + = 572.4; [M + Na] + = 594.4; [2M + H] + = 1142.8; [2M + Na] + = 1164.9.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（１９ｅ）
１９ａと同様の合成手順で２ｊおよび１７ａから１９ｅを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (19e)
A similar synthetic procedure to 19a was used to obtain 19e from 2j and 17a.

白色粉末。収率４７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.52 (d, J= 9.0 Hz, 2H), 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 7.17 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 16.5 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 6.16 (brs, NH), 5.04 (brs, NH), 4.34-4.33 (m, 1H), 4.26-4.22 (m, 1H),
4.17-4.16 (m, 1H), 3.56-3.54 (m, 2H), 3.13-3.09 (m, 1H), 3.07-3.02 (m, 1H), 1.42 (s, 9H). Mass found [M - Boc + H]+= 498.3; [M + Na]+ = 620.4; [2M + H]+ = 1194.9; [2M + Na]+= 1216.9。 White powder. Yield 47%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.52 (d, J= 9.0Hz, 2H), 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 7.17 (d, J = 9.0Hz, 2H), 7.07 (d, J = 16.5Hz, 1H), 6.99 (d, J = 16.5Hz, 1H), 6.66 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 6.16 (brs, NH), 5.04 (brs, NH), 4.34-4.33 (m, 1H), 4.26-4.22 (m, 1H),
4.17-4.16 (m, 1H), 3.56-3.54 (m, 2H), 3.13-3.09 (m, 1H), 3.07-3.02 (m, 1H), 1.42 (s, 9H). Mass found [M - Boc + H] + = 498.3; [M + Na] + = 620.4; [2M + H] + = 1194.9; [2M + Na] + = 1216.9.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジエトキシスチリル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（１９ｆ）
１９ａと同様の合成手順で２ｊおよび１７ｂから１９ｆを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-diethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (19f)
Following a similar synthetic procedure to 19a, 19f was obtained from 2j and 17b.

白色粉末。収率４７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 9.0 Hz, 2H), 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 7.16 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 16.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.64 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 6.15 (brs, NH), 5.04 (brs, NH), 4.33-4.32 (m, 1H), 4.26-4.22 (m, 1H),
4.17-4.16 (m, 1H), 4.06 (q, J = 7.0 Hz, 4H), 3.59-3.51 (m, 2H), 3.13-3.09 (m, 1H), 3.07-3.02 (m, 1H), 1.44-1.42 (m, 15H). Mass found [M - Boc + H]+= 519.2; [M + H]+ = 619.2; [M + Na]+= 641.2; [2M + Na]+ = 1259.5。 White powder. Yield 47%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.51 (d, J= 9.0Hz, 2H), 7.33-7.30 (m, 2H), 7.25-7.21 (m, 3H), 7.16 (d, J = 9.0Hz, 2H), 7.05 (d, J = 16.0Hz, 1H), 6.97 (d, J = 16.0Hz, 1H), 6.64 (d, J= 2.0Hz, 2H), 6.40 (t, J= 2.0Hz, 1H), 6.15 (brs, NH), 5.04 (brs, NH), 4.33-4.32 (m, 1H), 4.26-4.22 (m, 1H),
4.17-4.16 (m, 1H), 4.06 (q, J = 7.0 Hz, 4H), 3.59-3.51 (m, 2H), 3.13-3.09 (m, 1H), 3.07-3.02 (m, 1H), 1.44-1.42 (m, 15H). Mass found [M - Boc + H] + = 519.2; [M + H] + = 619.2; [M + Na] + = 641.2; [2M + Na] + = 1259.5.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）－２－メトキシフェノキシ）カルボニル）オキシ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（１９ｇ）
１９ａと同様の合成手順で２ｃおよび１７ｃから１９ｇを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)-2-methoxyphenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19 g)
The synthesis of 19g was obtained from 2c and 17c by a similar procedure to that of 19a.

白色粉末。収率３７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.11-7.08 (m, 3H), 7.05 (d, J = 16.0 Hz, 1H), 6.98 (d, J = 16.0 Hz, 1H), 6.67 (s, 2H), 6.41 (s, 1H), 6.37 (brs, NH), 5.04 (brs, NH), 4.34 (t, J = 5.5 Hz, 2H), 3.98-3.92 (m, 4H), 3.84
(s, 6H), 3.69-3.65 (m, 2H), 2.17-2.16 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H]+ = 474.3; [M + H]+= 574.4; [M + Na]+ = 596.4。 White powder. Yield: 37%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.11-7.08 (m, 3H), 7.05 (d, J = 16.0Hz, 1H), 6.98 (d, J = 16.0Hz, 1H), 6.67 (s, 2H), 6.41 (s, 1H), 6.37 (brs, NH), 5.04 (brs, NH), 4.34 (t, J = 5.5 Hz, 2H), 3.98-3.92 (m, 4H), 3.84
(s, 6H), 3.69-3.65 (m, 2H), 2.17-2.16 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H] + = 474.3; [M + H] + = 574.4; [M + Na] + = 596.4.

ｔｅｒｔ－ブチル（１－（（２－（（（４－（（１Ｅ，３Ｅ）－４－（３，５－ジメトキシフェニル）ブタ－１，３－ジエン－１－イル）フェノキシ）カルボニル）オキシ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（１９ｈ）
１９ａと同様の合成手順で２ｃおよび１７ｄから１９ｈを得た。 tert-Butyl (1-((2-(((4-((1E,3E)-4-(3,5-dimethoxyphenyl)buta-1,3-dien-1-yl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (19h)
Following a similar synthetic procedure to 19a, 19h was obtained from 2c and 17d.

白色粉末。収率３５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.45 (d, J= 9.0 Hz, 2H), 7.15 (d, J= 9.0 Hz, 2H), 6.95-6.86 (m, 2H), 6.67 (d, J = 16.5 Hz, 1H), 6.63 (d, J = 16.5 Hz, 1H), 6.60 (d, J = 2.0 Hz, 2H), 6.38 (t, J = 2.0 Hz, 1H), 6.37 (brs, NH), 5.03 (brs, NH), 4.33 (t, J = 5.5 Hz, 2H), 3.93-3.90 (m, 1H), 3.83 (s, 6H), 3.70-3.61 (m, 2H), 2.18-2.16 (m, 1H), 1.45 (s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H]+ = 470.0; [M + H]+= 570.3; [M + Na]+ = 592.3。 White powder. Yield 35%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.45 (d, J= 9.0Hz, 2H), 7.15 (d, J= 9.0Hz, 2H), 6.95-6.86 (m, 2H), 6.67 (d, J = 16.5Hz, 1H), 6.63 (d, J = 16.5Hz, 1H), 6.60 (d, J = 2.0Hz, 2H), 6.38 (t, J = 2.0Hz, 1H), 6.37 (brs, NH), 5.03 (brs, NH), 4.33 (t, J = 5.5Hz, 2H), 3.93-3.90 (m, 1H), 3.83 (s, 6H), 3.70-3.61 (m, 2H), 2.18-2.16 (m, 1H), 1.45 (s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H] + = 470.0; [M + H] + = 570.3; [M + Na] + = 592.3.

（Ｅ）－２－（２－アミノアセトアミド）エチル（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェニル）カーボネート塩酸塩（６ａ）
ＤＣＭ（２０ｍＬ）中の化合物１９ａ（６３９ｍｇ，１．３ｍｍｏｌ）の撹拌溶液に１，４－ジオキサン（６．３ｍＬ）中の４Ｍ ＨＣｌを加え、室温で３時間撹拌した。その後、反応溶液を蒸発させ、分取ＨＰＬＣ精製（バッファーとしてＴＦＡ、詳細なグラジエント溶出は下記情報を参照のこと）に供した。その後、水性画分を濃塩酸数滴で処理し、凍結乾燥して化合物６ａ（４９１ｍｇ，収率９２％）を白色固体として得た。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.15 (
d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.5 Hz, 2H), 6.40 (t, J= 2.5 Hz, 1H), 4.34 (t, J= 5.5 Hz, 2H), 3.71 (s, 2H), 3.62 (t, J = 5.5 Hz, 2H);
13C-NMR (CD3OD, 125 MHz), δ(ppm): 166.23, 161.14, 153.66, 150.50, 139.18, 135.49, 128.98, 127.40, 127.18, 120.95, 104.18, 99.58, 66.72, 40.06, 38.13; Mass found [M - HCl + H]+ = 408.3; [M - HCl + Na]+= 430.2; [2M - 2HCl + H]+ = 814.5; [2M
-2HCl + Na]+ = 836.5。 (E)-2-(2-aminoacetamido)ethyl (4-(3,5-bis(methoxy-d3)styryl-d6)phenyl)carbonate hydrochloride (6a)
To a stirred solution of compound 19a (639 mg, 1.3 mmol) in DCM (20 mL) was added 4M HCl in 1,4-dioxane (6.3 mL) and stirred at room temperature for 3 h. The reaction solution was then evaporated and subjected to preparative HPLC purification (TFA as buffer, detailed gradient elution see information below). The aqueous fraction was then treated with a few drops of concentrated hydrochloric acid and lyophilized to give compound 6a (491 mg, 92% yield) as a white solid. 1 H-NMR (CD 3 OD, 500 MHz), δ(ppm): 7.58 (d, J= 8.5 Hz, 2H), 7.18 (d, J= 8.5 Hz, 2H), 7.15 (
d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.5 Hz, 2H), 6.40 (t, J= 2.5 Hz, 1H), 4.34 (t, J= 5.5 Hz, 2H), 3.71 (s, 2H), 3.62 (t, J = 5.5 Hz, 2H);
13C -NMR (CD3OD , 125MHz), δ(ppm): 166.23, 161.14, 153.66, 150.50, 139.18, 135.49, 128.98, 127.40, 127.18, 120.95, 104.18, 99.58, 66.72, 40.06, 38.13; Mass found [M - HCl + H] + = 408.3; [M - HCl + Na] + = 430.2; [2M - 2HCl + H] + = 814.5; [2M
-2HCl + Na] + = 836.5.

カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３ Ｃ１８，５ｕｍ，３０＊２５０ｍｍ
流量：３８ｍｌ／分
溶媒Ａ：Ｈ２Ｏ中１０％ＡＣＮ＋０．１％ＴＦＡ
溶媒Ｂ：Ｈ２Ｏ中９０％ＡＣＮ＋０．１％ＴＦＡ
グラジエント： Column: Inertsil ODS-3 C18, 5um, 30*250mm
Flow rate: 38 ml/min Solvent A: 10% ACN + 0.1% TFA in H2O
Solvent B: 90% ACN + 0.1% TFA in H2O
Gradient:

最終化合物６ｂ～６ｈは、前記６ａに記載した実験手順で調製したが、いくつかの重要ではない変更を加えた。 Final compounds 6b-6h were prepared using the experimental procedure described in 6a above, with some minor modifications.

（Ｅ）－２－（２－アミノアセトアミド）エチル（４－（３，５－ジエトキシスチリル）フェニル）カーボネート塩酸塩（６ｂ）
６ａと同様の合成手順で１９ｂから６ｂを得た。 (E)-2-(2-aminoacetamido)ethyl(4-(3,5-diethoxystyryl)phenyl)carbonate hydrochloride (6b)
Following a similar synthetic procedure to 6a, 19b gave 6b.

白色粉末。収率９５％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.13 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 16.5 Hz, 1H), 6.69 (d, J= 2.5 Hz, 2H), 6.38 (t, J= 2.5 Hz, 1H), 4.34 (t, J= 5.5 Hz, 2H), 4.06-4.02 (m, 4H), 3.71 (s, 2H), 3.62 (t, J = 5.5 Hz, 2H), 1.39 (t, J = 7.0 Hz, 6H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 166.24, 160.36, 153.66, 150.48, 139.09, 135.51, 129.06, 127.27, 127.16, 120.93, 104.74, 100.71, 66.72, 63.15, 40.08, 38.14, 13.77; Mass found [M - HCl + H]+= 430.3; [M - HCl + Na]+ = 452.2; [2M - 2HCl + H]+
= 858.5; [2M - 2HCl + Na]+ = 880.5。 White powder. Yield 95%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.17 (d, J= 9.0Hz, 2H), 7.13 (d, J= 16.5Hz, 1H), 7.07 (d, J= 16.5Hz, 1H), 6.69 (d, J= 2.5Hz, 2H), 6.38 (t, J= 2.5Hz, 1H), 4.34 (t, J= 5.5Hz, 2H), 4.06-4.02 (m, 4H), 3.71 (s, 2H), 3.62 (t, J = 5.5Hz, 2H), 1.39 (t, J = 7.0Hz, 6H); 13C -NMR (CD 3 OD, 125 MHz), δ(ppm): 166.24, 160.36, 153.66, 150.48, 139.09, 135.51, 129.06, 127.27, 127.16, 120.93, 104.74, 100.71, 66.72, 63.15, 40.08, 38.14, 13.77; Mass found [M - HCl + H] + = 430.3; [M - HCl + Na] + = 452.2; [2M - 2HCl + H] +
= 858.5; [2M - 2HCl + Na] + = 880.5.

（Ｅ）－２－（２－アミノ－３－メチルブタンアミド）エチル ４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェニル）カーボネート塩酸塩（６ｃ）
６ａと同様の合成手順で１９ｃから６ｃを得た。 (E)-2-(2-amino-3-methylbutanamido)ethyl 4-(3,5-bis(methoxy-d3)styryl-d6)phenyl)carbonate hydrochloride (6c)
Following a similar synthetic procedure to 6a, 6c was obtained from 19c.

白色固体。収率８９％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.08 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.5 Hz, 2H), 6.40 (t, J= 2.5 Hz, 1H), 4.40-4.32 (m, 1H), 4.31-4.29 (m, 1H), 3.73-3.72 (m, 1H), 3.67 (d, J = 6.0 Hz, 1H), 3.54-3.49 (m, 1H), 2.22-2.16 (m, 1H), 1.08 (t, J = 6.5 Hz, 6H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.45,
161.14, 153.58, 150.50, 139.18, 135.50, 128.98, 127.40, 127.17, 120.93, 104.19, 99.58, 66.62, 58.46, 38.04, 30.09, 17.37, 16.60; Mass found [M - HCl + H]+ = 449.3; [M - HCl + Na]+ = 471.3; [2M - 2HCl + Na]+= 919.4。 White solid. Yield 89%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.17 (d, J= 9.0Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.08 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.5Hz, 2H), 6.40 (t, J= 2.5Hz, 1H), 4.40-4.32 (m, 1H), 4.31-4.29 (m, 1H), 3.73-3.72 (m, 1H), 3.67 (d, J = 6.0Hz, 1H), 3.54-3.49 (m, 1H), 2.22-2.16 (m, 1H), 1.08 (t, J = 6.5 Hz, 6H); 13C -NMR ( CD3OD , 125 MHz), δ(ppm): 168.45,
161.14, 153.58, 150.50, 139.18, 135.50, 128.98, 127.40, 127.17, 120.93, 104.19, 99.58, 66.62, 58.46, 38.04, 30.09, 17.37, 16.60; Mass found [M - HCl + H] + = 449.3; [M - HCl + Na] + = 471.3; [2M - 2HCl + Na] + = 919.4.

（Ｅ）－２－（２－アミノ－３－メチルブタンアミド）エチル（４－（３，５－ジエトキシスチリル）フェニル）カーボネート塩酸塩（６ｄ）
６ａと同様の合成手順で１９ｄから６ｄを得た。 (E)-2-(2-amino-3-methylbutanamido)ethyl(4-(3,5-diethoxystyryl)phenyl)carbonate hydrochloride (6d)
Following a similar synthetic procedure to 6a, 6d was obtained from 19d.

白色固体。収率９３％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.58 (d, J= 9.0 Hz, 2H), 7.17 (d, J= 9.0 Hz, 2H), 7.13 (d, J= 16.0 Hz, 1H), 7.06 (d, J= 16.0 Hz, 1H), 6.69 (d, J= 2.0 Hz, 2H), 6.38 (t, J= 2.0 Hz, 1H), 4.40-4.34 (m, 1H), 4.33-4.30 (m, 1H), 4.06-4.02 (m, 4H), 3.77-3.72 (m, 1H), 3.66 (d, J= 6.0 Hz, 1H), 3.54-3.49
(m, 1H), 2.23-2.16 (m, 1H), 1.39 (t, J = 7.0 Hz, 6H), 1.08 (t, J = 7.0 Hz, 6H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.48, 160.36, 153.58, 150.47, 139.10, 135.52, 129.06, 127.28, 127.16, 120.93, 104.77, 100.73, 66.62, 63.16, 58.48, 38.05, 30.10, 17.37, 16.62, 13.78; Mass found [M - HCl + H]+ = 472.3; [M - HCl + Na]+ = 494.3; [2M - 2HCl + H]+ = 942.6; [2M - 2HCl + Na]+ = 964.6。 White solid. Yield 93%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.58 (d, J= 9.0Hz, 2H), 7.17 (d, J= 9.0Hz, 2H), 7.13 (d, J= 16.0Hz, 1H), 7.06 (d, J= 16.0Hz, 1H), 6.69 (d, J= 2.0Hz, 2H), 6.38 (t, J= 2.0Hz, 1H), 4.40-4.34 (m, 1H), 4.33-4.30 (m, 1H), 4.06-4.02 (m, 4H), 3.77-3.72 (m, 1H), 3.66 (d, J= 6.0Hz, 1H), 3.54-3.49
(m, 1H), 2.23-2.16 (m, 1H), 1.39 (t, J = 7.0 Hz, 6H), 1.08 (t, J = 7.0 Hz, 6H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 168.48, 160.36, 153.58, 150.47, 139.10, 135.52, 129.06, 127.28, 127.16, 120.93, 104.77, 100.73, 66.62, 63.16, 58.48, 38.05, 30.10, 17.37, 16.62, 13.78; Mass found [M - HCl [M - HCl + Na] + = 472.3; [M - HCl + Na] + = 494.3; [2M - 2HCl + H] + = 942.6; [2M - 2HCl + Na] + = 964.6.

（Ｅ）－２－（２－アミノ－３－フェニルプロパンアミド）エチル ４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェニル）カーボネート塩酸塩（６ｅ）
６ａと同様の合成手順で１９ｅから６ｅを得た。 (E)-2-(2-amino-3-phenylpropanamido)ethyl 4-(3,5-bis(methoxy-d3)styryl-d6)phenyl)carbonate hydrochloride (6e)
Following a similar synthetic procedure to 6a, 19e gave 6e.

白色固体。収率９０％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.59 (d, J= 9.0 Hz, 2H), 7.39-7.36 (m, 2H), 7.32-7.29 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 16.5 Hz, 1H), 7.08 (d, J = 16.5 Hz, 1H), 6.71 (d, J= 1.5 Hz, 2H), 6.40 (s, 1H), 4.27-4.19 (m, 2H), 4.06 (t, J = 7.0 Hz, 1H), 3.66-3.61 (m, 1H), 3.48-3.43 (m, 1H), 3.19 (dd, J = 7.0, 13.5 Hz, 1H), 3.08 (dd, J = 7.0, 13.5 Hz, 1H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.48, 161.14, 153.51, 150.50, 139.18, 135.50, 134.15, 129.13, 129.00, 128.71, 127.48, 127.40, 127.19, 120.92, 104.20, 99.59, 66.66, 54.41, 38.03, 37.29; Mass found [M - HCl + H]+ = 498.2; [M - HCl + Na]+ = 520.4; [2M - 2HCl + H]+ = 994.6。 White solid. Yield 90%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.59 (d, J= 9.0Hz, 2H), 7.39-7.36 (m, 2H), 7.32-7.29 (m, 3H), 7.18 (d, J = 9.0Hz, 2H), 7.15 (d, J = 16.5Hz, 1H), 7.08 (d, J = 16.5Hz, 1H), 6.71 (d, J= 1.5Hz, 2H), 6.40 (s, 1H), 4.27-4.19 (m, 2H), 4.06 (t, J = 7.0Hz, 1H), 3.66-3.61 (m, 1H), 3.48-3.43 (m, 1H), 3.19 (dd, J = 7.0, 13.5 Hz, 1H), 3.08 (dd, J = 7.0, 13.5 Hz, 1H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 168.48, 161.14, 153.51, 150.50, 139.18, 135.50, 134.15, 129.13, 129.00, 128.71, 127.48, 127.40, 127.19, 120.92, 104.20, 99.59, 66.66, 54.41, 38.03, 37.29; Mass found [M - HCl + H] + = 498.2; [M - HCl + Na] + = 520.4; [2M - 2HCl + H] + = 994.6.

（Ｅ）－２－（２－アミノ－３－フェニルプロパンアミド）エチル（４－（３，５－ジエトキシスチリル）フェニル）カーボネート塩酸塩（６ｆ）
６ａと同様の合成手順で１９ｆから６ｆを得た。 (E)-2-(2-amino-3-phenylpropanamido)ethyl(4-(3,5-diethoxystyryl)phenyl)carbonate hydrochloride (6f)
Following a similar synthetic procedure to 6a, 6f was obtained from 19f.

白色固体。収率９２％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.57 (d, J= 8.5 Hz, 2H), 7.38-7.35 (m, 2H), 7.32-7.29 (m, 3H), 7.17 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 16.5 Hz, 1H), 7.05 (d, J = 16.5 Hz, 1H), 6.68 (d, J= 2.0 Hz, 2H), 6.38 (t, J= 2.0 Hz, 1H), 4.24-4.20 (m, 2H), 4.07-4.02 (m, 5H), 3.65-3.60 (m, 1H), 3.48-3.43 (m, 1H), 3.19 (dd, J= 7.5, 14.0 Hz, 1H), 3.08 (dd, J = 7.5, 14.0 Hz, 1H), 1.38 (t,
J = 7.5 Hz, 6H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.48, 160.36, 153.51, 150.47, 139.10, 135.52, 134.15, 129.12, 129.07, 128.71, 127.48, 127.27, 127.18, 120.91, 104.77, 100.74, 66.65, 63.16, 54.41, 38.03, 37.29, 13.78; Mass found [M - HCl + H]+ = 519.2; [2M - 2HCl + H]+ = 1037.4。 White solid. Yield 92%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.57 (d, J= 8.5Hz, 2H), 7.38-7.35 (m, 2H), 7.32-7.29 (m, 3H), 7.17 (d, J = 8.5Hz, 2H), 7.12 (d, J = 16.5Hz, 1H), 7.05 (d, J = 16.5Hz, 1H), 6.68 (d, J= 2.0Hz, 2H), 6.38 (t, J= 2.0Hz, 1H), 4.24-4.20 (m, 2H), 4.07-4.02 (m, 5H), 3.65-3.60 (m, 1H), 3.48-3.43 (m, 1H), 3.19 (dd, J = 7.5, 14.0 Hz, 1H), 3.08 (dd, J = 7.5, 14.0 Hz, 1H), 1.38 (t,
J = 7.5 Hz, 6H); 13 C-NMR (CD 3 OD, 125 MHz), δ(ppm): 168.48, 160.36, 153.51, 150.47, 139.10, 135.52, 134.15, 129.12, 129.07, 128.71, 127.48, 127.27, 127.18, 120.91, 104.77, 100.74, 66.65, 63.16, 54.41, 38.03, 37.29, 13.78; Mass found [M - HCl + H] + = 519.2; [2M - 2HCl + H] + = 1037.4.

（Ｅ）－２－（２－アミノ－３－メチルブタンアミド）エチル（４－（３，５－ジメトキシスチリル）－２－メトキシフェニル）カーボネート塩酸塩（６ｇ）
６ａと同様の合成手順で１９ｇから６ｇを得た。 (E)-2-(2-amino-3-methylbutanamido)ethyl(4-(3,5-dimethoxystyryl)-2-methoxyphenyl)carbonate hydrochloride (6 g)
6g was obtained from 19g by the same synthetic procedure as for 6a.

白色固体。収率８５％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.29 (d, J= 1.5 Hz, 1H), 7.17-7.13 (m, 2H), 7.12-7.07 (m, 2H), 6.73 (d, J = 2.0 Hz, 2H), 6.41 (t, J = 2.0 Hz, 1H), 4.38-4.28 (m, 2H), 3.90 (s, 3H), 3.80 (s, 6H), 3.75-3.64 (m, 2H), 3.54-3.51 (m, 1H), 2.20 (s, 1H), 1.08 (t, J= 7.0 Hz, 6H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.43, 161.14, 153.30, 151.30, 139.40, 139.18, 136.92, 129.09, 127.81, 121.97, 118.72, 110.16, 104.24, 99.61, 66.65, 58.47, 55.10, 54.39, 38.11, 30.10, 17.41, 16.63; Mass found [M - HCl + H]+ = 474.2; [M - HCl + Na]+ = 496.2; [2M - 2HCl + H]+ = 946.5; [2M - 2HCl + Na]+ = 968.5。 White solid. Yield 85%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.29 (d, J= 1.5Hz, 1H), 7.17-7.13 (m, 2H), 7.12-7.07 (m, 2H), 6.73 (d, J = 2.0Hz, 2H), 6.41 (t, J = 2.0Hz, 1H), 4.38-4.28 (m, 2H), 3.90 (s, 3H), 3.80 (s, 6H), 3.75-3.64 (m, 2H), 3.54-3.51 (m, 1H), 2.20 (s, 1H), 1.08 (t, J= 7.0Hz, 6H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 168.43, 161.14, 153.30, 151.30, 139.40, 139.18, 136.92, 129.09, 127.81, 121.97, 118.72, 110.16, 104.24, 99.61, 66.65, 58.47, 55.10, 54.39, 38.11, 30.10, 17.41, 16.63; Mass found [M - HCl + H] + = 474.2; [M - HCl + Na] + = 496.2; [2M - 2HCl + H] + = 946.5; [2M - 2HCl + Na] + = 968.5.

２－（２－アミノ－３－メチルブタンアミド）エチル（４－（（１Ｅ，３Ｅ）－４－（３，５－ジメトキシフェニル）ブタ－１，３－ジエン－１－イル）フェニル）カーボネート塩酸塩（６ｈ）
６ａと同様の合成手順で１９ｈから６ｈを得た。 2-(2-amino-3-methylbutanamido)ethyl (4-((1E,3E)-4-(3,5-dimethoxyphenyl)buta-1,3-dien-1-yl)phenyl)carbonate hydrochloride (6h)
Following a similar synthetic procedure to 6a, 6h was obtained from 19h.

白色固体。収率８０％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.49 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 8.5 Hz, 2H), 7.01-6.95 (m, 2H), 6.71-6.62 (m, 4H), 6.38 (s, 1H), 4.39-4.35 (m, 1H), 4.33-4.29 (m, 1H), 3.78 (s, 6H), 3.77-3.71 (m, 1H), 3.68 (d, J = 6.0 Hz, 1H), 3.53-3.49 (m, 1H), 2.22-2.18 (m, 1H), 1.07 (t, J = 7.0 Hz, 6H);
13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.46, 161.09, 153.56, 150.39, 139.36, 135.65, 133.01, 131.38, 129.53, 129.33, 126.99, 120.94, 104.09, 99.55, 66.62, 58.45,
54.39, 38.04, 30.09, 17.37, 16.63; Mass found [M - HCl + H]+= 469.0; [M - HCl +
Na]+ = 491.1; [2M - 2HCl + H]+ = 937.0。 White solid. Yield 80%. 1H -NMR (CD3OD , 500MHz), δ(ppm): 7.49 (d, J= 8.5Hz, 2H), 7.14 (d, J= 8.5Hz, 2H), 7.01-6.95 (m, 2H), 6.71-6.62 (m, 4H), 6.38 (s, 1H), 4.39-4.35 (m, 1H), 4.33-4.29 (m, 1H), 3.78 (s, 6H), 3.77-3.71 (m, 1H), 3.68 (d, J = 6.0Hz, 1H), 3.53-3.49 (m, 1H), 2.22-2.18 (m, 1H), 1.07 (t, J = 7.0Hz, 6H);
13C -NMR (CD3OD , 125MHz), δ(ppm): 168.46, 161.09, 153.56, 150.39, 139.36, 135.65, 133.01, 131.38, 129.53, 129.33, 126.99, 120.94, 104.09, 99.55, 66.62, 58.45,
54.39, 38.04, 30.09, 17.37, 16.63; Mass found [M - HCl + H] + = 469.0; [M - HCl +
[Na] + = 491.1; [2M - 2HCl + H] + = 937.0.

１－２－６．目的化合物７ａ～７ｆの合成
スキーム６に従って、化合物７ａ～７ｆを合成した。 1-2-6. Synthesis of target compounds 7a to 7f Compounds 7a to 7f were synthesized according to Scheme 6.

示すように、ベンジルＮ－（２－アミノエチル）カルバメート塩酸塩とＮ－Ｂｏｃ－アミノ酸（化合物１ａ、１ｃおよび１ｊ）とを、ＥＤＣＩおよびＤＭＡＰの存在下で反応させ、対応するアミド誘導体（化合物２０ａ～２０ｃ）を得た。化合物２０ａ～２０ｃをＰｄ／Ｃ上で水素化し、対応する化合物２１ａ～２１ｃを得た。一方、プテロスチルベンまたは１７ａをＮＥｔ３の存在下でトリホスゲンで処理して対応する２２ａ～２２ｂを得て、これをさらに精製せずに化合物２１ａ～２１ｃと別々に反応させて対応する２３ａ～２３ｆを得た。その後、２３ａ～２３ｆを１，４－ジオキサン中４Ｍ ＨＣｌで脱保護し、目的化合物７ａ～７ｆを得た。 As shown, benzyl N-(2-aminoethyl)carbamate hydrochloride was reacted with N-Boc-amino acids (compounds 1a, 1c and 1j) in the presence of EDCI and DMAP to give the corresponding amide derivatives (compounds 20a-20c). Compounds 20a-20c were hydrogenated over Pd/C to give the corresponding compounds 21a-21c. Meanwhile, pterostilbene or 17a was treated with triphosgene in the presence of NEt3 to give the corresponding 22a-22b, which was reacted separately with compounds 21a-21c without further purification to give the corresponding 23a-23f. 23a-23f were then deprotected with 4M HCl in 1,4-dioxane to give the target compounds 7a-7f.

スキーム６：化合物７ａ～７ｆの合成 Scheme 6: Synthesis of compounds 7a-7f

試薬および条件：（ａ）ＥＤＣＩ，ＤＩＰＥＡ，ＣＨ２Ｃｌ２，室温，１２時間；（ｂ）１０％Ｐｄ／Ｃ，ＭｅＯＨ，室温，１２時間；（ｃ）トリエチルアミン，０℃から室温，１．５時間；（ｄ）トリメチルアミン，室温，１．５時間；（ｅ）１，４－ジオキサン中４Ｍ ＨＣｌ。 Reagents and conditions: (a) EDCI, DIPEA, CH 2 Cl 2 , rt, 12 h; (b) 10% Pd/C, MeOH, rt, 12 h; (c) triethylamine, 0° C. to rt, 1.5 h; (d) trimethylamine, rt, 1.5 h; (e) 4M HCl in 1,4-dioxane.

ベンジル（２－（２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）アセトアミド）エチル）カルバメート（２０ａ）
ＣＨ２Ｃｌ２（８０ｍＬ）中のベンジル（２－アミノエチル）カルバメートＨＣｌ（８．５ｇ，３６．８ｍｍｏｌ），Ｂｏｃ－Ｇｌｙ－ＯＨ １ａ（５．３ｇ，３０．４ｍｍｏｌ）およびＤＩＰＥＡ（９．５ｇ，７３．６ｍｍｏｌ）の撹拌溶液にＥＤＣＩ（８．６ｇ，４５．０ｍｍｏｌ）を加え、反応混合物を室温にて１２時間撹拌した。反応後、溶媒を減圧下で除去し、残渣をカラムクロマトグラフィー（ｎ－ヘキサンからＥＡ／ｎ－ヘキサン＝１／５（Ｖ／Ｖ））で精製し、目的物２０ａ（８．０ｇ，収率７４％）を白色粉末と
して得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.33-7.30 (m, 5H), 6.86 (brs, NH), 5.56 (brs, NH), 5.07 (s, 2H), 3.71 (s, 2H), 3.37-3.30 (m, 4H), 1.42 (s, 9H).
ベンジル（２－（２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタンアミド）エチル）カルバメート（２０ｂ）
２０ａと同様の合成手順で１ｃから２０ｂを得た。 Benzyl (2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)carbamate (20a)
To a stirred solution of benzyl(2-aminoethyl)carbamate HCl (8.5 g, 36.8 mmol), Boc-Gly-OH 1a (5.3 g, 30.4 mmol) and DIPEA (9.5 g, 73.6 mmol) in CH 2 Cl 2 (80 mL) was added EDCI (8.6 g, 45.0 mmol), and the reaction mixture was stirred at room temperature for 12 h. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (n-hexane to EA/n-hexane=1/5 (V/V)) to obtain the target compound 20a (8.0 g, 74% yield) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.33-7.30 (m, 5H), 6.86 (brs, NH), 5.56 (brs, NH), 5.07 (s, 2H), 3.71 (s, 2H), 3.37-3.30 (m, 4H), 1.42 (s, 9H).
Benzyl (2-(2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)ethyl)carbamate (20b)
20b was obtained from 1c via a similar synthetic procedure to 20a.

白色粉末。収率４１％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.34-7.31 (m, 5H), 6.55 (brs, NH), 5.35 (brs, NH), 5.05 (s, 2H), 5.03 (brs, NH), 3.86-3.83 (m, 1H), 3.40-3.33 (m, 4H), 2.12-2.10 (m, 1H), 1.42 (s, 9H), 0.93 (d, J= 7.0 Hz, 3H), 0.88 (d, J= 7.0 Hz, 3H)。 White powder. Yield: 41%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.34-7.31 (m, 5H), 6.55 (brs, NH), 5.35 (brs, NH), 5.05 (s, 2H), 5.03 (brs , NH), 3.86-3.83 (m, 1H), 3.40-3.33 (m, 4H), 2.12-2.10 (m, 1H), 1.42 (s, 9H), 0.93 (d, J= 7.0 Hz, 3H), 0.88 (d, J= 7.0 Hz, 3H).

ベンジル（２－（２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－フェニルプロパンアミド）エチル）カルバメート（２０ｃ）
２０ａと同様の合成手順で１ｊから２０ｃを得た。 Benzyl (2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropanamido)ethyl)carbamate (20c)
Following a similar synthetic procedure to 20a, 20c was obtained from 1j.

白色粉末。収率４８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.36-7.18 (m, 11H), 6.18 (brs, NH), 5.07 (s, 2H), 5.04 (brs, NH), 4.26 (d, J = 7.0 Hz, 1H), 3.48-3.17 (m, 4H), 3.04-3.01 (m, 2H), 1.40 (s, 9H)。 White powder. Yield: 48%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.36-7.18 (m, 11H), 6.18 (brs, NH), 5.07 (s, 2H), 5.04 (brs, NH), 4.26 (d , J = 7.0 Hz, 1H), 3.48-3.17 (m, 4H), 3.04-3.01 (m, 2H), 1.40 (s, 9H).

ｔｅｒｔ－ブチル（２－（（２－アミノエチル）アミノ）－２－オキソエチル）カルバメート（２１ａ）
化合物２０ａ（４．０ｇ，１１．４ｍｍ）をＭｅＯＨ（５０ｍＬ）に溶解させ、１０％Ｐｄ／Ｃ（０．６ｇ）で処理し、反応混合物を水素雰囲気下において室温で１２時間撹拌した。反応混合物をセライトで濾過した。濾液の溶媒を蒸発させ、残渣をカラムクロマトグラフィー（ＣＨ２Ｃｌ２／メタノール＝１／１９（Ｖ／Ｖ））で精製して、化合物２１ａ（２．３５ｇ，９５％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.16 (brs, NH), 5.62 (brs, NH), 3.79 (brs, 2H), 3.38-3.36 (m, 2H), 2.90-2.88 (m,
2H), 1.42 (s, 9H)。 tert-Butyl (2-((2-aminoethyl)amino)-2-oxoethyl)carbamate (21a)
Compound 20a (4.0 g, 11.4 mm) was dissolved in MeOH (50 mL) and treated with 10% Pd/C (0.6 g), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The reaction mixture was filtered through Celite. The solvent of the filtrate was evaporated, and the residue was purified by column chromatography (CH 2 Cl 2 /methanol = 1/19 (V/V)) to obtain compound 21a (2.35 g, 95%) as a white powder. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 7.16 (brs, NH), 5.62 (brs, NH), 3.79 (brs, 2H), 3.38-3.36 (m, 2H), 2.90-2.88 (m,
2H), 1.42 (s, 9H).

ｔｅｒｔ－ブチル（１－（（２－アミノエチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（２１ｂ）
２１ａと同様の合成手順で２０ｂから２１ｂを得た。 tert-Butyl (1-((2-aminoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (21b)
21b was obtained from 20b via a similar synthetic procedure to 21a.

白色粉末。収率９５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 6.93 (brs, NH), 5.24 (brs, NH), 3.89-3.86 (m, 1H), 3.40-3.37 (m, 1H), 3.32-3.29 (m, 1H), 2.87-2.85 (m,
2H), 2.13-2.09 (m, 1H), 1.42 (s, 9H), 0.94 (d, J = 7.0 Hz, 3H), 0.91 (d, J= 7.0
Hz, 3H)。 White powder. Yield: 95%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 6.93 (brs, NH), 5.24 (brs, NH), 3.89-3.86 (m, 1H), 3.40-3.37 (m, 1H), 3.32 -3.29 (m, 1H), 2.87-2.85 (m,
2H), 2.13-2.09 (m, 1H), 1.42 (s, 9H), 0.94 (d, J = 7.0 Hz, 3H), 0.91 (d, J= 7.0
Hz, 3H).

ｔｅｒｔ－ブチル（１－（（２－アミノエチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（２１ｃ）
２１ａと同様の合成手順で２０ｃから２１ｃを得た。 tert-Butyl (1-((2-aminoethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (21c)
21c was obtained from 20c via a similar synthetic procedure to 21a.

白色粉末。収率９５％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.29-7.19 (m, 5H), 6.77 (brs, NH), 5.34 (s, NH), 4.32-4.31 (m, 1H), 3.24-3.23 (m, 2H), 3.06-3.02 (m, 2H), 2.79 (s, 2H), 2.71 (s, NH2), 1.37 (s, 9H)。 White powder. Yield: 95%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.29-7.19 (m, 5H), 6.77 (brs, NH), 5.34 (s, NH), 4.32-4.31 (m, 1H), 3.24 -3.23 (m, 2H), 3.06-3.02 (m, 2H), 2.79 (s, 2H), 2.71 (s, NH2 ), 1.37 (s, 9H).

ｔｅｒｔ－ブチル（Ｅ）－（２－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）アミノ）エチル）アミノ）－２－オキソエチル）カルバメート（２３ａ）
脱水ＣＨ２Ｃｌ２（１５ｍｌ）中のプテロスチルベン（１．４１ｇ，５．５１ｍｍｏｌ
）およびトリホスゲン（０．５４ｇ，１．８２ｍｍ）の溶液に、トリエチルアミン（１．３６ｇ，１３．４ｍｍｏｌ）を０℃で滴下して加えた。反応混合物を０℃で３０分間撹拌した後、室温に温め、中間体２２ａの溶液を得た。脱水ＣＨ２Ｃｌ２（１５ｍｌ）中の化合物２１ａ（１．１７ｇ，５．９ｍｍｏｌ）およびトリエチルアミン（１．３６ｇ，１３．４ｍｍｏｌ）の溶液を中間体２２ａの溶液に滴下して加えた。得られた混合物をさらに１．５時間撹拌した。反応後、溶媒を真空下で除去し、残渣をＥＡに取り込み、飽和クエン酸水溶液で洗浄した。有機層を回収し、Ｎａ２ＳＯ４上で乾燥させ、蒸発させた。残渣をカラムクロマトグラフィー（シリカゲル、０～６７％のＥｔＯＡｃ／ｎ－ヘキサン）で精製し、粗生成物を得た。粗生成物を分取ＨＰＬＣ（７０％ＡＣＮ，３０％Ｈ２Ｏ）で精製し、目的化合物２３ａ（０．８６ｇ，二段階収率３２％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.47 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.96 (d, J= 16.0 Hz, 1H), 6.70 (brs, NH), 6.65 (d, J =
2.5 Hz, 2H), 6.40 (t, J = 2.5 Hz, 1H), 5.74 (brs, NH), 5.19 (brs, NH), 3.83 (s,
6H), 3.79 (d, J= 5.5 Hz, 2H), 3.50-3.46 (m, 2H), 3.43-3.40 (m, 2H), 1.44 (s, 9H). Mass found [M + Na]+ = 522.0, [2M + Na]+ = 1021.3。 tert-Butyl (E)-(2-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl)amino)-2-oxoethyl)carbamate (23a)
Pterostilbene (1.41 g, 5.51 mmol) in dry CH2Cl2 ( 15 ml)
To a solution of 21a (1.17 g, 5.9 mmol) and triphosgene (0.54 g, 1.82 mm) was added triethylamine (1.36 g, 13.4 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature to give a solution of intermediate 22a. A solution of compound 21a (1.17 g, 5.9 mmol) and triethylamine (1.36 g, 13.4 mmol) in dry CH 2 Cl 2 (15 ml) was added dropwise to the solution of intermediate 22a. The resulting mixture was stirred for another 1.5 h. After the reaction, the solvent was removed under vacuum and the residue was taken up in EA and washed with saturated aqueous citric acid. The organic layer was collected, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography (silica gel, 0-67% EtOAc/n-hexane) to give the crude product. The crude product was purified by preparative HPLC (70% ACN, 30% H2O ) to give the target compound 23a (0.86 g, 32% yield in two steps) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.47 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.96 (d, J= 16.0 Hz, 1H), 6.70 (brs, NH), 6.65 (d, J =
2.5 Hz, 2H), 6.40 (t, J = 2.5 Hz, 1H), 5.74 (brs, NH), 5.19 (brs, NH), 3.83 (s,
6H), 3.79 (d, J= 5.5 Hz, 2H), 3.50-3.46 (m, 2H), 3.43-3.40 (m, 2H), 1.44 (s, 9H). Mass found [M + Na] + = 522.0, [2M + Na] + = 1021.3.

ｔｅｒｔ－ブチル（Ｅ）－（２－（（２－（（（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）カルボニル）アミノ）エチル）アミノ）－２－オキソエチル）カルバメート（２３ｂ）
２３ａと同様の合成手順で２１ａおよび２２ｂから２３ｂを得た。 tert-Butyl (E)-(2-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)amino)ethyl)amino)-2-oxoethyl)carbamate (23b)
23b was obtained from 21a and 22b via a similar synthetic procedure to 23a.

白色粉末。収率２７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.96 (d, J= 16.0 Hz, 1H), 6.69 (brs, NH), 6.65 (d, J = 2.0 Hz, 2H), 6.39 (t, J = 2.0 Hz, 1H), 5.73 (brs, NH), 5.19 (brs, NH), 3.79 (d, J = 5.5 Hz, 2H) , 3.49-3.47 (m, 2H), 3.43-3.40 (m, 2H), 1.44 (s, 9H). Mass found [M + Na]+ = 528.2, [2M + Na]+ = 1033.4。 White powder. Yield 27%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.96 (d, J= 16.0 Hz, 1H), 6.69 (brs, NH), 6.65 (d, J = 2.0 Hz, 2H), 6.39 (t, J = 2.0 Hz, 1H), 5.73 (brs, NH), 5.19 (brs, NH), 3.79 (d, J = 5.5 Hz, 2H), 3.49-3.47 (m, 2H), 3.43-3.40 (m, 2H), 1.44 (s, 9H). Mass found [M + Na] + = 528.2, [2M + Na] + = 1033.4.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）アミノ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（２３ｃ）
２３ａと同様の合成手順で２１ｂおよび２２ａから２３ｃを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (23c)
23c was obtained from 21b and 22a via a similar synthetic procedure to 23a.

白色粉末。収率１８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.10 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.97 (d, J= 16.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.52 (brs, NH), 6.40 (t, J = 2.0 Hz, 1H), 5.77 (brs, NH), 5.03 (brs, NH), 3.87-3.85 (m, 1H), 3.83 (s, 6H), 3.47-3.41 (m, 4H), 2.18-2.16
(m, 1H) 1.45 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 0.93 (d, J= 7.0 Hz, 3H). Mass found [M - Boc + H]+ = 443.3; [M + H]+ = 543.4; [M + Na]+ = 565.3。 White powder. Yield 18%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.10 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.0 Hz, 1H), 6.97 (d, J= 16.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.52 (brs, NH), 6.40 (t, J = 2.0 Hz, 1H), 5.77 (brs, NH), 5.03 (brs, NH), 3.87-3.85 (m, 1H), 3.83 (s, 6H), 3.47-3.41 (m, 4H), 2.18-2.16
(m, 1H) 1.45 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M - Boc + H] + = 443.3; [M + H] + = 543.4; [M + Na] + = 565.3.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）カルボニル）アミノ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（２３ｄ）
２３ａと同様の合成手順で２１ｂおよび２２ｂから２３ｄを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)amino)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (23d)
Following a similar synthetic procedure to 23a, 23d was obtained from 21b and 22b.

白色粉末。収率２８％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.5 Hz, 2H), 7.06 (d, J= 16.0 Hz, 1H), 6.97 (d, J= 16.0 Hz, 1H), 6.65 (d, J= 2.0 Hz, 2H), 6.47 (brs, NH), 6.39 (t, J = 2.5Hz, 1H), 5.73 (brs, NH), 5.00 (brs, NH), 3.87-3.84 (m, 1H) , 3.52-3.42 (m, 4H), 2.17-2.14 (m, 2H), 1.45
(s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M + Na]+ = 570.3, [2M + Na]+ = 1117.6。 White powder. Yield 28%. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.48 (d, J= 8.5Hz, 2H), 7.11 (d, J= 8.5Hz, 2H), 7.06 (d, J= 16.0Hz, 1H), 6.97 (d, J= 16.0Hz, 1H), 6.65 (d, J= 2.0Hz, 2H), 6.47 (brs, NH), 6.39 (t, J = 2.5Hz, 1H), 5.73 (brs, NH), 5.00 (brs, NH), 3.87-3.84 (m, 1H), 3.52-3.42 (m, 4H), 2.17-2.14 (m, 2H), 1.45
(s, 9H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass found [M + Na] + = 570.3, [2M + Na] + = 1117.6.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）アミノ）エチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（２３ｅ）
２３ａと同様の合成手順で２１ｃおよび２２ａから２３ｅを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (23e)
Following a similar synthetic procedure to 23a, 23e was obtained from 21c and 22a.

白色粉末。収率２７％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.35-7.27 (m, 3H), 7.23-7.22 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 16.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 6.15 (brs, NH), 5.42 (brs, NH), 5.03 (brs, NH), 4.31-4.26 (m, 1H), 3.81 (s, 6H), 3.38-3.33 (m, 2H), 3.31-3.25 (m, 2H), 3.11-3.03 (m, 2H), 1.45 (s, 9H). Mass found [M - Boc + H]+ = 491.0; [M + H]+= 591.4; [M + Na]+ = 613.3。 White powder. Yield 27%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.35-7.27 (m, 3H), 7.23-7.22 (m, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 16.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 2H), 6.40 (t, J= 2.0 Hz, 1H), 6.15 (brs, NH), 5.42 (brs, NH), 5.03 (brs, NH), 4.31-4.26 (m, 1H), 3.81 (s, 6H), 3.38-3.33 (m, 2H), 3.31-3.25 (m, 2H), 3.11-3.03 (m, 2H), 1.45 (s, 9H). Mass found [M - Boc + H] + = 491.0; [M + H] + = 591.4; [M + Na] + = 613.3.

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェノキシ）カルボニル）アミノ）エチル）アミノ）－１－オキソ－３－フェニルプロパン－２－イル）カルバメート（２３ｆ）
２３ａと同様の合成手順で２１ｃおよび２２ｂから２３ｆを得た。 tert-Butyl (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)amino)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (23f)
Following a similar synthetic procedure to 23a, 23f was obtained from 21c and 22b.

白色粉末。収率３０％。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.34-7.27 (m, 3H), 7.25-7.22 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 16.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.65 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 6.19 (brs, NH), 5.44 (brs, NH), 5.05 (brs, NH), 4.31-4.27 (m, 1H), 3.38-3.33 (m, 2H), 3.32-3.24 (m, 2H), 3.11-3.03 (m, 2H), 1.41 (s, 9H). Mass found [M - Boc + H]+ = 497.3; [M + H]+ = 597.4; [M + Na]+ = 619.5; [2M + H]+ = 1192.9;
[2M + Na]+ = 1214.8。 White powder. Yield 30%. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.48 (d, J= 8.5 Hz, 2H), 7.34-7.27 (m, 3H), 7.25-7.22 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 16.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.65 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 6.19 (brs, NH), 5.44 (brs, NH), 5.05 (brs, NH), 4.31-4.27 (m, 1H), 3.38-3.33 (m, 2H), 3.32-3.24 (m, 2H), 3.11-3.03 (m, 2H), 1.41 (s, 9H). Mass found [M - Boc + H] + = 497.3; [M + H] + = 597.4; [M + Na] + = 619.5; [2M + H] + = 1192.9;
[2M + Na] + = 1214.8.

（Ｅ）－４－（３，５－ジメトキシスチリル）フェニル（２－（２－アミノアセトアミド）エチル）カルバメート塩酸塩（７ａ）
ＤＣＭ（１０ｍＬ）中の化合物２３ａ（７６０ｍｇ，１．５ｍｍｏｌ）の撹拌溶液に１，４－ジオキサン（７．６０ｍＬ）中の４Ｍ ＨＣｌを加え、混合物を室温で３時間撹拌した。反応混合物を蒸発させ、分取ＨＰＬＣ精製にかけた（バッファーとしてＴＦＡ、詳細なグラジエント溶出は下記情報を参照のこと）。その後、水性画分を濃塩酸数滴で処理し、凍結乾燥して化合物７ａ（６１４ｍｇ、収率９３％）を白色固体として得た。1H-NMR
(CD3OD, 500 MHz), δ(ppm): 7.55 (d, J= 8.0 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.10 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.70 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 3.80 (s, 6H), 3.42-3.40 (m, 2H), 3.35-3.31 (m, 4H); 13C-NMR (CD3OD, 125
MHz), δ(ppm): 166.19, 161.13, 155.99, 150.61, 139.31, 134.66, 128.46, 127.67, 127.01, 121.56, 104.16, 99.52, 54.40, 40.10, 39.94, 39.12; Mass found [M - HCl +
H]+= 400.2; [2M - 2HCl + H]+ = 799.3。 (E)-4-(3,5-dimethoxystyryl)phenyl(2-(2-aminoacetamido)ethyl)carbamate hydrochloride (7a)
To a stirred solution of compound 23a (760 mg, 1.5 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (7.60 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated and subjected to preparative HPLC purification (TFA as buffer, detailed gradient elution see information below). The aqueous fraction was then treated with a few drops of concentrated hydrochloric acid and lyophilized to give compound 7a (614 mg, 93% yield) as a white solid. 1 H-NMR
( CD3OD , 500 MHz), δ(ppm): 7.55 (d, J= 8.0 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.10 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.70 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 3.80 (s, 6H), 3.42-3.40 (m, 2H), 3.35-3.31 (m, 4H); 13C -NMR ( CD3OD , 125
MHz), δ(ppm): 166.19, 161.13, 155.99, 150.61, 139.31, 134.66, 128.46, 127.67, 127.01, 121.56, 104.16, 99.52, 54.40, 40.10, 39.94, 39.12; Mass found [M - HCl +
[2M - 2HCl + H] + = 400.2; [2M - 2HCl + H] + = 799.3.

カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３ Ｃ１８，５ｕｍ，３０＊２５０ｍｍ
流量：３８ｍｌ／分
溶媒Ａ：Ｈ２Ｏ中１０％ＡＣＮ＋０．１％ＴＦＡ
溶媒Ｂ：Ｈ２Ｏ中９０％ＡＣＮ＋０．１％ＴＦＡ
グラジエント： Column: Inertsil ODS-3 C18, 5um, 30*250mm
Flow rate: 38 ml/min Solvent A: 10% ACN + 0.1% TFA in H2O
Solvent B: 90% ACN + 0.1% TFA in H2O
Gradient:

（Ｅ）－４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェニル（２－（２－アミノアセトアミド）エチル）カルバメート塩酸塩（７ｂ）
７ａと同様の合成手順で２３ｂから７ｂを得た。 (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenyl(2-(2-aminoacetamido)ethyl)carbamate hydrochloride (7b)
7b was obtained from 23b via a similar synthetic procedure to 7a.

白色固体。収率９５％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.55 (d, J= 8.0 Hz, 2H), 7.13 (d, J= 16.5 Hz, 1H), 7.10 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.70 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 3.42-3.40 (m, 2H), 3.35-3.31 (m, 4H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 166.19, 161.13, 155.99, 150.61, 139.31, 134.66, 128.47, 127.66, 127.01, 121.56, 104.13, 99.50, 40.10, 39.94, 39.12; Mass found [M - HCl + H]+ = 406.3; [2M - 2HCl + H]+= 811.3。 White solid. Yield 95%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.55 (d, J= 8.0Hz, 2H), 7.13 (d, J= 16.5Hz, 1H), 7.10 (d, J= 8.0Hz, 2H), 7.05 (d, J= 16.5Hz, 1H), 6.70 (d, J= 2.0Hz, 2H), 6.39 (t, J= 2.0Hz, 1H), 3.42-3.40 (m, 2H), 3.35-3.31 (m, 4H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 166.19, 161.13, 155.99, 150.61, 139.31, 134.66, 128.47, 127.66, 127.01, 121.56, 104.13, 99.50, 40.10, 39.94, 39.12; Mass found [M - HCl + H] + = 406.3; [2M - 2HCl + H] + = 811.3.

（Ｅ）－４－（３，５－ジメトキシスチリル）フェニル（２－（２－アミノ－３－メチルブタンアミド）エチル）カルバメート塩酸塩（７ｃ）
７ａと同様の合成手順で２３ｃから７ｃを得た。 (E)-4-(3,5-dimethoxystyryl)phenyl(2-(2-amino-3-methylbutanamido)ethyl)carbamate hydrochloride (7c)
7c was obtained from 23c via a similar synthetic procedure to 7a.

白色固体。収率９２％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.56 (d, J= 9.0 Hz, 2H), 7.15 (d, J= 16.5 Hz, 1H), 7.09 (d, J= 9.0 Hz, 2H), 7.06 (d, J= 16.5 Hz, 1H), 6.71 (d, J= 2.5 Hz, 2H), 6.40 (t, J= 2.5 Hz, 1H), 3.80 (s, 6H), 3.61 (d, J = 5.5
Hz, 1H), 3.50-3.45 (m, 1H), 3.41-3.35 (m, 3H), 2.21-2.17 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.44, 161.13, 155.92, 150.57, 139.30, 134.67, 128.47, 127.65, 127.01, 121.54, 104.14, 99.49, 58.57, 54.37, 39.96, 38.97, 29.97, 17.51, 16.52; Mass found [M - HCl + H]+ = 443.0; [M - HCl + Na]+ = 465.2; [2M - 2HCl + H]+ = 884.5; [2M - 2HCl + Na]+ = 906.5。 White solid. Yield: 92%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.56 (d, J= 9.0Hz, 2H), 7.15 (d, J= 16.5Hz, 1H), 7.09 (d, J= 9.0Hz, 2H), 7.06 (d, J= 16.5Hz, 1H), 6.71 (d, J= 2.5Hz, 2H), 6.40 (t, J= 2.5Hz, 1H), 3.80 (s, 6H), 3.61 (d, J = 5.5
Hz, 1H), 3.50-3.45 (m, 1H), 3.41-3.35 (m, 3H), 2.21-2.17 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H); 13C -NMR (CD 3 OD, 125 MHz), δ(ppm): 168.44, 161.13, 155.92, 150.57, 139.30, 134.67, 128.47, 127.65, 127.01, 121.54, 104.14, 99.49, 58.57, 54.37, 39.96, 38.97, 29.97, 17.51, 16.52; Mass found [M - HCl + H] + = 443.0; [M - HCl + Na] + = 465.2; [2M - 2HCl + H] + = 884.5; [2M - 2HCl + Na] + = 906.5.

（Ｅ）－４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェニル（２－（２－アミノ－３－メチルブタンアミド）エチル）カルバメート塩酸塩（７ｄ）
７ａと同様の合成手順で２３ｄから７ｄを得た。 (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenyl(2-(2-amino-3-methylbutanamido)ethyl)carbamate hydrochloride (7d)
7d was obtained from 23d via a similar synthetic procedure to 7a.

白色固体。収率９３％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.55 (d, J= 8.5 Hz, 2H), 7.14 (d, J= 16.5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.70 (d, J= 1.5 Hz, 2H), 6.39 (t, J= 1.5 Hz, 1H), 3.65 (d, J= 5.0 Hz, 1H), 3.64-3.35 (m, 4H), 2.23-2.16 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H);13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.45, 161.12, 155.90, 150.58, 139.31, 134.66, 128.47, 127.65, 127.01, 121.54, 104.13, 99.49, 58.57, 39.96, 38.96, 29.97, 17.51, 16.55; Mass found [M - HCl + H]+ = 448.3; [M - HCl + Na]+ = 470.2; [2M - 2HCl + Na]+ = 1149.5。 White solid. Yield 93%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.55 (d, J= 8.5Hz, 2H), 7.14 (d, J= 16.5Hz, 1H), 7.09 (d, J= 8.5Hz, 2H), 7.05 (d, J= 16.5Hz, 1H), 6.70 (d, J= 1.5Hz, 2H), 6.39 (t, J= 1.5Hz, 1H), 3.65 (d, J= 5.0Hz, 1H), 3.64-3.35 (m, 4H), 2.23-2.16 (m, 1H), 1.07 (d, J = 7.0Hz, 3H), 1.05 (d, J = 7.0Hz, 3H); 13C -NMR (CD3OD , 125MHz), δ(ppm): 168.45, 161.12, 155.90, 150.58, 139.31, 134.66, 128.47, 127.65, 127.01, 121.54, 104.13, 99.49, 58.57, 39.96, 38.96, 29.97, 17.51, 16.55; Mass found [M-HCl + H] + = 448.3; [M-HCl + Na] + = 470.2; [2M-2HCl + Na] + = 1149.5.

（Ｅ）－４－（３，５－ジメトキシスチリル）フェニル（２－（２－アミノ－３－フェニルプロパンアミド）エチル）カルバメート塩酸塩（７ｅ）
７ａと同様の合成手順で２３ｅから７ｅを得た。 (E)-4-(3,5-dimethoxystyryl)phenyl(2-(2-amino-3-phenylpropanamido)ethyl)carbamate hydrochloride (7e)
7e was obtained from 23e via a similar synthetic procedure to 7a.

白色固体。収率９０％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.53 (d, J= 8.5 Hz, 2H), 7.41-7.31 (m, 2H), 7.33-7.29 (m, 3H), 7.13 (d, J = 17.0 Hz, 1H), 7.09 (d, J =
8.5 Hz, 2H), 7.04 (d, J = 17.0 Hz, 1H), 6.70 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 4.04 (t, J = 7.0 Hz, 1H), 3.80 (s, 6H), 3.75-3.57 (m, 1H), 3.40-3.34 (m, 2H), 3.28-3.20 (m, 2H), 3.08-3.04 (m, 1H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.50, 161.12, 155.91, 150.55, 139.30, 134.68, 134.31, 129.09, 128.75, 128.47, 127.65, 127.49, 127.02, 121.55, 104.15, 99.50, 54.52, 54.39, 39.84, 39.04, 37.26; Mass found [M - HCl + H]+= 491.2; [M - HCl + Na]+ = 513.3; [2M - 2HCl + H]+ = 980.5。 White solid. Yield: 90%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.53 (d, J= 8.5Hz, 2H), 7.41-7.31 (m, 2H), 7.33-7.29 (m, 3H), 7.13 ( d, J = 17.0 Hz, 1H), 7.09 (d, J =
8.5 Hz, 2H), 7.04 (d, J = 17.0 Hz, 1H), 6.70 (d, J= 2.0 Hz, 2H), 6.40 (s, 1H), 4.04 (t, J = 7.0 Hz, 1H), 3.80 (s, 6H), 3.75-3.57 (m, 1H), 3.40-3.34 (m, 2H), 3.28-3.20 (m, 2H), 3.08-3.04 (m, 1H); 13C -NMR ( CD3OD , 125 MHz), δ(ppm): 168.50, 161.12, 155.91, 150.55, 139.30, 134.68, 134.31, 129.09, 128.75, 128.47, 127.65, 127.49, 127.02, 121.55, 104.15, 99.50, 54.52, 54.39, 39.84, 39.04, 37.26; Mass found [M - HCl + H] + = 491.2; [M - HCl + Na] + = 513.3; [2M - 2HCl + H] + = 980.5.

（Ｅ）－４－（３，５－ビス（メトキシ－ｄ３）スチリル－ｄ６）フェニル（２－（２－アミノ－３－フェニルプロパンアミド）エチル）カルバメート塩酸塩（７ｆ）
７ａと同様の合成手順で２３ｆから７ｆを得た。 (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenyl(2-(2-amino-3-phenylpropanamido)ethyl)carbamate hydrochloride (7f)
7f was obtained from 23f via a similar synthetic procedure to 7a.

白色固体。収率９６％。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.53 (d, J= 9.0 Hz, 2H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 3H), 7.13 (d, J = 17.0 Hz, 1H), 7.09 (d, J =
9.0 Hz, 2H), 7.04 (d, J = 17.0 Hz, 1H), 6.69 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 4.05 (t, J= 7.0 Hz, 1H), 3.39-3.34 (m, 2H), 3.29-3.20 (m, 3H), 3.08-3.04 (m, 1H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 168.48, 161.13, 155.89, 150.56, 139.30, 134.69, 134.31, 129.09, 128.74, 128.49, 127.64, 127.49, 127.00, 121.55, 104.14, 99.50, 54.52, 39.84, 39.04, 37.26; Mass found [M - HCl + H]+ = 496.3; [2M - 2HCl + H]+ = 991.4。 White solid. Yield: 96%. 1H -NMR ( CD3OD , 500MHz), δ(ppm): 7.53 (d, J= 9.0Hz, 2H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 3H), 7.13 ( d, J = 17.0 Hz, 1H), 7.09 (d, J =
9.0 Hz, 2H), 7.04 (d, J = 17.0 Hz, 1H), 6.69 (d, J= 2.0 Hz, 2H), 6.39 (t, J= 2.0 Hz, 1H), 4.05 (t, J= 7.0 Hz , 1H), 3.39-3.34 (m, 2H), 3.29-3.20 (m, 3H), 3.08-3.04 (m, 1H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 168.48 , 161.13, 155.89, 150.56, 139.30, 134.69, 134.31, 129.09, 128.74, 128.49, 127.64, 127.49, 127.00, 121.55, 104.14, 99.50, 54.52, 39.84, 39.04, 37.26; Mass found [M - HCl + H] + = 496.3; [2M - 2HCl + H] + = 991.4.

１－２－７．目的化合物８の合成
スキーム７において、化合物８の合成を記載した。示すように、２－ヒドロキシエチルアセテートをＮＥｔ３およびＤＭＡＰの存在下でｔｅｒｔ－ブチルクロロジフェニルシラン（ＴＰＤＰＳ－Ｃｌ）と反応させて化合物２４を得て、これをさらにナトリウムメトキシド（ＮａＯＭｅ）で脱アセチル化して化合物２５を得た。化合物２５をＥＤＣＩおよびＤＭＡＰの存在下でＢｏｃ－Ｖａｌ－ＯＨ（１ｃ）とカップリングさせて化合物２６を得て、その後、ＴＢＤＰＳ基をＴＢＡＦで脱保護して水酸化物化合物２７を得た。化合物２７をｐ－ニトロフェニルクロロホルメートと反応させ、対応する化合物２８を得て、これをさらに精製せずにプテロスチルベンと反応させ、期待される炭酸塩２９を得て、その後Ｂｏｃ基を脱保護して目的化合物８を得た。 1-2-7. Synthesis of target compound 8 In scheme 7, the synthesis of compound 8 was described. As shown, 2-hydroxyethyl acetate was reacted with tert-butylchlorodiphenylsilane (TPDPS-Cl) in the presence of NEt 3 and DMAP to give compound 24, which was further deacetylated with sodium methoxide (NaOMe) to give compound 25. Compound 25 was coupled with Boc-Val-OH (1c) in the presence of EDCI and DMAP to give compound 26, after which the TBDPS group was deprotected with TBAF to give the hydroxide compound 27. Compound 27 was reacted with p-nitrophenyl chloroformate to give the corresponding compound 28, which was reacted with pterostilbene without further purification to give the expected carbonate 29, after which the Boc group was deprotected to give the target compound 8.

スキーム７：化合物８の合成 Scheme 7: Synthesis of compound 8

試薬および条件：（ａ）ＴＢＤＰＳ－Ｃｌ，トリメチルアミン，ＤＭＡＰ，ＣＨ２Ｃｌ２，１２時間；（ｂ）メタノール中５．４Ｍ ＮａＯＭｅ，ＭｅＯＨ，２時間；（ｃ）Ｂｏｃ－Ｖａｌ－ＯＨ １ｃ，ＥＤＣＩ，トリエチルアミン，ＤＭＡＰ，ＣＨ２Ｃｌ２，１２時間；（ｄ）ＴＨＦ中の１．０Ｍ ＴＢＡＦ，ＴＨＦ，１時間，７２％；（ｅ）トリエチルアミン，ＣＨ２Ｃｌ２，０℃；（ｆ）ＤＭＡＰ，ＡＣＮ，５０℃；（ｇ）１，４－ジオキサン中の４Ｍ ＨＣｌ，３時間。 Reagents and conditions: (a) TBDPS-Cl, trimethylamine, DMAP, CH 2 Cl 2 , 12 hours; (b) 5.4 M NaOMe in methanol, MeOH, 2 hours; (c) Boc-Val-OH 1c, EDCI, triethylamine, DMAP, CH 2 Cl 2 , 12 hours; (d) 1.0 M TBAF in THF, THF, 1 hour, 72%; (e) triethylamine, CH 2 Cl 2 , 0° C.; (f) DMAP, ACN, 50° C.; (g) 4 M HCl in 1,4-dioxane, 3 hours.

２－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）エチルアセテート（２４）
ＣＨ２Ｃｌ２（２５ｍＬ）中の２－ヒドロキシエチルアセテート（３．１２ｇ，３０．０ｍｍｏｌ）の撹拌溶液にｔｅｒｔ－ブチルクロロジフェニルシラン（ＴＢＤＰＳ－Ｃｌ）（８．６５ｇ，３１．５ｍｍｏｌ），Ｅｔ３Ｎ（４．６ｍＬ，３３．０ｍｍｏｌ）およびＤＭＡＰ（１１０ｍｇ，０．９ｍｍｏｌ）を加え、出発原料が完全に消費されるまで（１２時間）、室温で撹拌した。反応混合物をＣＨ２Ｃｌ２（２５ｍＬ）で希釈し、水（２５ｍＬ）で洗浄した。有機層を乾燥させ（Ｎａ２ＳＯ４）、濾過し、蒸発させた。残渣をフラッシュクロマトグラフィー（シリカゲル、０％～２％のＥｔＯＡｃ／ｎ－ヘキサン）に供し、化合物２４を無色オイルとして得た（４．５９ｇ，収率４３％）。1H-NMR (500 MHz, CDCl3), δ(ppm): 7.69-7.67 (m, 4H), 7.43-7.37 (m, 6H), 4.18 (t, J = 4.5 Hz,
2H), 3.85 (t, J = 4.5 Hz, 2H), 2.03 (s, 3H), 1.06 (s, 9H)。 2-((tert-butyldiphenylsilyl)oxy)ethyl acetate (24)
To a stirred solution of 2-hydroxyethyl acetate (3.12 g, 30.0 mmol) in CH 2 Cl 2 (25 mL) were added tert-butylchlorodiphenylsilane (TBDPS-Cl) (8.65 g, 31.5 mmol), Et 3 N (4.6 mL, 33.0 mmol) and DMAP (110 mg, 0.9 mmol) and stirred at room temperature until the starting material was completely consumed (12 h). The reaction mixture was diluted with CH 2 Cl 2 (25 mL) and washed with water (25 mL). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated. The residue was subjected to flash chromatography (silica gel, 0% to 2% EtOAc/n-hexane) to give compound 24 as a colorless oil (4.59 g, 43% yield). 1H -NMR (500 MHz, CDCl3 ), δ(ppm): 7.69-7.67 (m, 4H), 7.43-7.37 (m, 6H), 4.18 (t, J = 4.5 Hz,
2H), 3.85 (t, J = 4.5 Hz, 2H), 2.03 (s, 3H), 1.06 (s, 9H).

２－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）エタノール（２５）
ＭｅＯＨ（１００ｍＬ）中の化合物２４（４５８９ｍｇ，１３．４ｍｍｏｌ）の撹拌溶液に、ＭｅＯＨ中５．４Ｍナトリウムメトキシド（４．９６ｍＬ，２６．８ｍｍｏｌ）を滴下して加えた。混合物を室温で２時間撹拌した。溶媒を真空中で蒸発させ、残渣をフラッシュクロマトグラフィー（シリカゲル、０～１７％のＥｔＯＡｃ／ｎ－ヘキサン）に供して、化合物２５を無色オイルとして得た（４．００ｇ、収率９９％）。1H-NMR (500 MH
z, CDCl3), δ(ppm): 7.71-7.67 (m, 4H), 7.45-7.37 (m, 6H), 3.77 (t, J = 4.5 Hz, 2H), 3.68 (t, J = 4.5 Hz, 2H), 1.58 (brs, OH, 1H), 1.05 (s, 9H)。 2-((tert-butyldiphenylsilyl)oxy)ethanol (25)
To a stirred solution of compound 24 (4589 mg, 13.4 mmol) in MeOH (100 mL) was added dropwise 5.4 M sodium methoxide in MeOH (4.96 mL, 26.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was subjected to flash chromatography (silica gel, 0-17% EtOAc/n-hexane) to give compound 25 as a colorless oil (4.00 g, 99% yield). 1 H-NMR (500 MH
z, CDCl3 ), δ(ppm): 7.71-7.67 (m, 4H), 7.45-7.37 (m, 6H), 3.77 (t, J = 4.5 Hz, 2H), 3.68 (t, J = 4.5 Hz, 2H), 1.58 (brs, OH, 1H), 1.05 (s, 9H).

２－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）エチル ２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタノエート（２６）
ＣＨ２Ｃｌ２（１００ｍＬ）中の化合物２５（２８７１ｍｇ，９．６ｍｍｏｌ），Ｂｏｃ－Ｖａｌ－ＯＨ １ｃ（２０７６ｍｇ，９．６ｍｍｏｌ）およびＮＥｔ３（１５９８ｕＬ，１１．５ｍｍｏｌ）の撹拌溶液に、ＥＤＣＩ（２１９８ｍｇ，１１．５ｍｍｏｌ）およびＤＭＡＰ（３５０ｍｇ，２．９ｍｍｏｌ）を添加した。反応混合物を室温で１２時間撹拌した。反応後、溶媒を真空除去し、残渣をカラムクロマトグラフィー（シリカゲル、０～５％ＥｔＯＡｃ／ｎ－ヘキサン）で精製し、目的生成物２６（２７１９ｍｇ，収率５７％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.67-7.66 (m, 4H),
7.44-7.26 (m, 6H), 5.03 (d, J = 8.5 Hz, NH, 1H), 4.25-4.11 (m, 3H), 3.88-3.85 (m, 2H), 2.15-2.04 (m, 1H), 1.44 (s, 9H), 1.04 (s, 9H), 0.94 (d, J = 6.5 Hz, 3H),
0.89 (d, J= 6.5 Hz, 3H)。 2-((tert-butyldiphenylsilyl)oxy)ethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (26)
To a stirred solution of compound 25 (2871 mg, 9.6 mmol), Boc-Val-OH 1c (2076 mg, 9.6 mmol) and NEt 3 (1598 uL, 11.5 mmol) in CH 2 Cl 2 (100 mL), EDCI (2198 mg, 11.5 mmol) and DMAP (350 mg, 2.9 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. After the reaction, the solvent was removed in vacuum and the residue was purified by column chromatography (silica gel, 0-5% EtOAc/n-hexane) to give the desired product 26 (2719 mg, 57% yield) as a white powder. 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 7.67-7.66 (m, 4H),
7.44-7.26 (m, 6H), 5.03 (d, J = 8.5 Hz, NH, 1H), 4.25-4.11 (m, 3H), 3.88-3.85 (m, 2H), 2.15-2.04 (m, 1H), 1.44 (s, 9H), 1.04 (s, 9H), 0.94 (d, J = 6.5 Hz, 3H),
0.89 (d, J= 6.5 Hz, 3H).

２－ヒドロキシエチル ２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタノエート（２７）
ＴＨＦ（２５ｍＬ）中の化合物２６（２７１９ｍｇ，５．４ｍｍｏｌ）の撹拌溶液に、ＴＨＦ中の１．０Ｍ ＴＢＡＦ（１０．８８ｍＬ，１０．９ｍｍｏｌ）を滴下して加えた。反応混合物を室温で１時間撹拌した。反応後、溶媒を真空除去し、残渣をカラムクロマトグラフィー（シリカゲル、０～３０％のＥｔＯＡｃ／ｎ－ヘキサン）で精製し、目的生成物２７（１０２２ｍｇ，収率７２％）を淡黄色オイルとして得た。1H-NMR (CDCl3, 500
MHz), δ(ppm): 5.00 (brs, 1H), 4.35-4.22 (m, 2H), 4.20-4.14 (m, 1H), 3.82 (s, 2H), 2.33 (brs, OH, 1H), 2.17-2.13 (m, 1H), 1.44 (s, 9H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H)。 2-Hydroxyethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (27)
To a stirred solution of compound 26 (2719 mg, 5.4 mmol) in THF (25 mL), 1.0 M TBAF in THF (10.88 mL, 10.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. After the reaction, the solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, 0-30% EtOAc/n-hexane) to give the desired product 27 (1022 mg, 72% yield) as a pale yellow oil. 1 H-NMR (CDCl 3 , 500
MHz), δ(ppm): 5.00 (brs, 1H), 4.35-4.22 (m, 2H), 4.20-4.14 (m, 1H), 3.82 (s, 2H), 2.33 (brs, OH, 1H), 2.17-2.13 (m, 1H), 1.44 (s, 9H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H).

（Ｅ）－２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル ２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタノエート（２９）
脱水ＣＨ２Ｃｌ２（２０ｍｌ）中の化合物２７（１０２２ｍｇ，３．９ｍｍｏｌ）の撹拌溶液にトリエチルアミン（１３６３ｕｌ，９．８ｍｍｏｌ）を加え、次に３０ｍＬ ＣＨ２Ｃｌ２中の４－ニトロフェニルクロロホルメート溶液（８６７ｍｇ，４．３ｍｍｏｌ）を０℃で滴下した。反応混合物を０℃で３０分間撹拌した後、室温に温めた。室温でさらに４時間撹拌した後、溶媒を真空下で除去して粗中間体２８を得て、これをＡＣＮ（３０ｍｌ）中のプテロスチルベン（１００２ｍｇ，３．９ｍｍｏｌ）およびＤＭＡＰ（９５６ｍｇ，７．８ｍｍｏｌ）と混合した。得られた混合物を５０℃まで１時間加熱した。反応後、溶媒を真空下で除去し、残渣をＥＡに取り込み、飽和クエン酸水溶液で洗浄した。有機層を回収し、Ｎａ２ＳＯ４上で乾燥させ、蒸発させた。残渣をカラムクロマトグラフィー（シリカゲル、０～３３％のＥｔＯＡｃ／ｎ－ヘキサン）で精製し、粗生成物を得た。粗生成物を分取ＨＰＬＣ（８０％ＡＣＮ，２０％Ｈ２Ｏ）で精製し、化合物２９（６００ｍｇ，二段階収率２８％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H), 7.06 (d, J= 16.0 Hz, 1H), 6.98 (d, J= 16.0 Hz, 1H), 6.66 (s, 2H), 6.41 (s, 2H), 5.02 (d, J = 9.5 Hz, NH, 1H), 4.52-4.45 (m, 3H), 4.42-4.39 (m, 1H), 4.30-4.29 (m, 1H), 3.83 (s, 6H), 2.19-2.17 (m, 1H) 1.45 (s, 9H), 0.99 (d, J = 6.5 Hz, 3H), 0.92 (d, J= 6.5 Hz, 3H). Mass
found [M - Boc + H]+ = 445.1; [M + H]+ = 545.1, [M + Na]+ = 567.1。 (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (29)
To a stirred solution of compound 27 (1022 mg, 3.9 mmol) in dry CH 2 Cl 2 (20 ml) was added triethylamine (1363 ul, 9.8 mmol), followed by dropwise addition of a solution of 4-nitrophenyl chloroformate (867 mg, 4.3 mmol) in 30 mL CH 2 Cl 2 at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for another 4 h, the solvent was removed under vacuum to give crude intermediate 28, which was mixed with pterostilbene (1002 mg, 3.9 mmol) and DMAP (956 mg, 7.8 mmol) in ACN (30 ml). The resulting mixture was heated to 50° C. for 1 h. After the reaction, the solvent was removed under vacuum and the residue was taken up in EA and washed with saturated aqueous citric acid. The organic layer was collected, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography (silica gel, 0-33% EtOAc/n-hexane) to give the crude product, which was purified by preparative HPLC (80% ACN, 20% H 2 O) to give compound 29 (600 mg, 28% yield for two steps) as a white powder. 1H -NMR ( CDCl3 , 500MHz), δ(ppm): 7.51 (d, J= 8.0Hz, 2H), 7.17 (d, J= 8.0Hz, 2H), 7.06 (d, J= 16.0Hz, 1H), 6.98 (d, J= 16.0Hz, 1H), 6.66 (s, 2H), 6.41 (s, 2H), 5.02 (d, J = 9.5Hz, NH, 1H), 4.52-4.45 (m, 3H), 4.42-4.39 (m, 1H), 4.30-4.29 (m, 1H), 3.83 (s, 6H), 2.19-2.17 (m, 1H) 1.45 (s, 9H), 0.99 (d, J = 6.5 Hz, 3H), 0.92 (d, J= 6.5 Hz, 3H). Mass
Found [M - Boc + H] + = 445.1; [M + H] + = 545.1, [M + Na] + = 567.1.

（Ｅ）－２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）オキシ）エチル ２－アミノ－３－メチルブタノエート塩酸塩（８）
５０ｍＬ丸ビンフラスコに化合物２９（５６１ｍｇ，１．０ｍｍｏｌ）および１，４－ジオキサン（５．１６ｍｌ）中の４Ｍ ＨＣｌを添加した。得られた混合物を室温で３時間撹拌した。溶媒を減圧下で除去した後、凍結乾燥し、目的生成物８を白色粉末として得た（４４６ｍｇ，収率９０％）。1H-NMR (CDCl3, 500 MHz), δ(ppm): 8.90 (brs, NH2, HCl, 3H), 7.48 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.96 (d, J= 16.0 Hz, 1H), 6.64 (s, 2H), 6.40 (s, 1H), 4.58-4.49 (m, 4H), 4.04 (s, 1H), 3.81 (s, 6H), 2.50 (s, 1H), 1.18-1.16 (m, 6H); 13C-NMR (CDCl3, 125 MHz), δ(ppm): 168.29, 160.99, 153.33, 150.30, 139.05, 135.34, 129.23, 127.90, 127.54, 121.30, 104.61, 100.14, 65.82, 63.39, 58.65, 55.37, 29.98, 18.35, 18.28; Mass found [M - HCl + H]+ = 445.2; [M - HCl + Na]+ = 467.2; [2M - 2HCl + H]+ = 888.6。 (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl 2-amino-3-methylbutanoate hydrochloride (8)
To a 50 mL round bottle flask was added compound 29 (561 mg, 1.0 mmol) and 4M HCl in 1,4-dioxane (5.16 ml). The resulting mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure, followed by lyophilization to give the desired product 8 as a white powder (446 mg, 90% yield). 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 8.90 (brs, NH2 , HCl, 3H), 7.48 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.96 (d, J = 16.0 Hz, 1H), 6.64 (s, 2H), 6.40 (s, 1H), 4.58-4.49 (m, 4H), 4.04 (s, 1H), 3.81 (s, 6H), 2.50 (s, 1H), 1.18-1.16 (m, 6H); 13C -NMR ( CDCl3 , 125 MHz), δ(ppm): 168.29, 160.99, 153.33, 150.30, 139.05, 135.34, 129.23, 127.90, 127.54, 121.30, 104.61, 100.14, 65.82, 63.39, 58.65, 55.37, 29.98, 18.35, 18.28; Mass found [M - HCl + H] + = 445.2; [M - HCl + Na] + = 467.2; [2M - 2HCl + H] + = 888.6.

１－２－８．目的化合物９の合成
スキーム８に従って、化合物９を合成した。示すように、アジ化ナトリウム（ＮａＮ３）による２－ブロモエタノールの置換反応により化合物３０が得られ、これをＥＤＣＩ活性化によりＢｏｃ－Ｖａｌ－ＯＨ（１ｃ）とカップリングしてエステル３１を得て、さらにＮ３基を水素化してアミン３２とした。化合物３２をｐ－ニトロフェニルクロロホルメートと反応させて対応するカルバメート３３を得て、これをさらに精製せずにプテロスチルベンと反応させて夾雑カルバメート３４を得て、その後Ｂｏｃ基を脱保護し、アミノ誘導体９を得た。 1-2-8. Synthesis of target compound 9 Compound 9 was synthesized according to scheme 8. As shown, the displacement reaction of 2-bromoethanol with sodium azide (NaN 3 ) gave compound 30, which was coupled with Boc-Val-OH (1c) by EDCI activation to give ester 31, and the N 3 group was further hydrogenated to give amine 32. Compound 32 was reacted with p-nitrophenyl chloroformate to give the corresponding carbamate 33, which was reacted with pterostilbene without further purification to give the contaminated carbamate 34, which was then deprotected from the Boc group to give the amino derivative 9.

スキーム８：化合物９の合成 Scheme 8: Synthesis of compound 9

試薬および条件：（ａ）ＮａＮ３，水，８０℃，２４時間；（ｂ）Ｂｏｃ－Ｖａｌ－ＯＨ １ｃ，ＥＤＣＩ，トリエチルアミン，ＤＭＡＰ，ＣＨ２Ｃｌ２，１２時間；（ｃ）Ｈ２，１０％Ｐｄ／Ｃ，ＥｔＯＡｃ，ＭｅＯＨ，２時間；（ｄ）トリエチルアミン，ＣＨ２
Ｃｌ２，０℃；（ｅ）ＤＭＡＰ，ＡＣＮ，５０℃，１時間；（ｆ）１，４－ジオキサン中４Ｍ ＨＣｌ，３時間。 Reagents and conditions: (a) NaN 3 , water, 80° C., 24 h; (b) Boc-Val-OH 1c, EDCI, triethylamine, DMAP, CH 2 Cl 2 , 12 h; (c) H 2 , 10% Pd/C, EtOAc, MeOH, 2 h; (d) triethylamine, CH 2
Cl 2 , 0° C.; (e) DMAP, ACN, 50° C., 1 h; (f) 4M HCl in 1,4-dioxane, 3 h.

２－アジドエタノール（３０）
１００ｍＬの丸底フラスコに２－ブロモエタノール（５８２７ｍｇ，４６．６ｍｍｏｌ）とアジ化ナトリウム（６０６２ｍｇ，９３．３ｍｍｏｌ）を水（５０ｍＬ）に溶解した溶液を加えた。混合物を８０℃で２４時間撹拌した後、室温まで冷却した。この溶液を酢酸エチル（３０ｍｌ×４）で抽出し，有機層をＮａ２ＳＯ４で乾燥し、濾過した。濾液の溶媒を蒸発させ、残渣をカラムクロマトグラフィー（シリカゲル、０～２５％のＥｔＯＡｃ／ｎ－ヘキサン）で精製し、目的化合物３０を淡黄色液体として得た（３７３５ｍｇ，収率９２％）。1H-NMR (CDCl3, 500 MHz), δ(ppm): 3.78 (d, J= 4.0 Hz, 2H), 3.45 (s, 2H), 1.86 (s, OH, 1H)。 2-Azidoethanol (30)
A solution of 2-bromoethanol (5827 mg, 46.6 mmol) and sodium azide (6062 mg, 93.3 mmol) in water (50 mL) was added to a 100 mL round-bottom flask. The mixture was stirred at 80° C. for 24 h and then cooled to room temperature. The solution was extracted with ethyl acetate (30 ml×4), and the organic layer was dried over Na 2 SO 4 and filtered. The filtrate was evaporated, and the residue was purified by column chromatography (silica gel, 0-25% EtOAc/n-hexane) to give the target compound 30 as a pale yellow liquid (3735 mg, 92% yield). 1 H-NMR (CDCl 3 , 500 MHz), δ(ppm): 3.78 (d, J= 4.0 Hz, 2H), 3.45 (s, 2H), 1.86 (s, OH, 1H).

２－アジドエチル ２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタノエート（３１）
ＣＨ２Ｃｌ２（５０ｍＬ）中の２－アジドエタノール３０（６８３ｍｇ，７．９ｍｍｏｌ），Ｂｏｃ－Ｖａｌ－ＯＨ １ｃ（１７０５ｍｇ，７．９ｍｍｏｌ）およびＮＥｔ３（１３１３ｕＬ，９．４ｍｍｏｌ）の撹拌溶液に、ＥＤＣＩ（１８０５ｍｇ，９．４ｍｍｏｌ）およびＤＭＡＰ（２８８ｍｇ，２．４ｍｍｏｌ）を添加した。反応混合物を室温で12時間撹拌した。反応後、溶媒を真空除去し、残渣をカラムクロマトグラフィー（シリカゲル、０～１１％のＥｔＯＡｃ／ｎ－ヘキサン）で精製し、目的生成物３１（１５２７ｍｇ，収率６８％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 4.99 (d, J= 6.5 Hz, NH, 1H), 4.31-4.27 (m, 3H), 3.51-3.50 (m, 2H), 2.18-2.17 (m, 1H), 1.44
(s, 9H), 0.95 (d, J= 6.5 Hz, 3H), 0.91 (d, J= 6.5 Hz, 3H)。 2-Azidoethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (31)
To a stirred solution of 2-azidoethanol 30 (683 mg, 7.9 mmol), Boc-Val-OH 1c (1705 mg, 7.9 mmol) and NEt 3 (1313 uL, 9.4 mmol) in CH 2 Cl 2 (50 mL) was added EDCI (1805 mg, 9.4 mmol) and DMAP (288 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 12 h. After the reaction, the solvent was removed in vacuum and the residue was purified by column chromatography (silica gel, 0-11% EtOAc/n-hexane) to give the desired product 31 (1527 mg, 68% yield) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 4.99 (d, J= 6.5 Hz, NH, 1H), 4.31-4.27 (m, 3H), 3.51-3.50 (m, 2H), 2.18-2.17 (m, 1H), 1.44
(s, 9H), 0.95 (d, J= 6.5 Hz, 3H), 0.91 (d, J= 6.5 Hz, 3H).

２－アミノエチル ２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタノエート（３２）
化合物３１の１５２７ｍｇを２５ｍＬのメタノールおよび２５ｍＬのＥＡに溶解させ、５６８ｍｇの１０％Ｐｄ／Ｃを加え、水素雰囲気下、室温で２時間撹拌した。Ｐｄ／Ｃを濾過し、１５ｍＬのメタノールで洗浄した。溶媒は真空下で除去した。残渣に水１０ｍＬを加えた後、凍結乾燥して生成物３２をオイルとして得た（１３１９ｍｇ，収率９５％）。1H-NMR (CDCl3, 500 MHz), δ(ppm): 5.08 (brs, NH, 1H), 4.20-4.10 (m, 1H), 3.86-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.49-3.41 (m, 1H), 3.01-2.97 (m, 1H), 2.30 (brs, NH2, 2H), 2.12 (s, 1H), 1.44 (s, 9H), 0.97-0.88 (m, 6H)。 2-Aminoethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (32)
1527 mg of compound 31 was dissolved in 25 mL of methanol and 25 mL of EA, and 568 mg of 10% Pd/C was added and stirred at room temperature under hydrogen atmosphere for 2 hours. Pd/C was filtered and washed with 15 mL of methanol. The solvent was removed under vacuum. 10 mL of water was added to the residue, which was then lyophilized to give product 32 as an oil (1319 mg, 95% yield). 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 5.08 (brs, NH, 1H), 4.20-4.10 (m, 1H), 3.86-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.49-3.41 (m, 1H), 3.01-2.97 (m, 1H), 2.30 (brs, NH2 , 2H), 2.12 (s, 1H), 1.44 (s, 9H), 0.97-0.88 (m, 6H).

（Ｅ）－２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）アミノ）エチル ２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）－３－メチルブタノエート（３４）
脱水ＣＨ２Ｃｌ２（３０ｍｌ）中の化合物３２（１４６９ｍｇ，５．６ｍｍｏｌ）の撹拌溶液にトリエチルアミン（１９６６ｕｌ，１４．１ｍｍｏｌ）を加え、次に４－ニトロフェニルクロロホルメート溶液（１２５１ｍｇ，６．２ｍｍｏｌ，３０ｍＬ ＣＨ２Ｃｌ２中）を０℃で滴下して添加した。反応混合物を０℃で３０分間撹拌した後、室温に温めた。室温でさらに４時間撹拌した後、溶媒を真空下で除去して粗中間体３３を得て、これをＡＣＮ（３０ｍｌ）中のプテロスチルベン（１４４６ｍｇ，５．６ｍｍｏｌ）およびＤＭＡＰ（１３７９ｍｇ，１１．３ｍｍｏｌ）と混合した。得られた混合物を５０℃に加熱して１時間反応させた。反応後、溶媒を蒸発させた。残渣をＥＡに取り込み、飽和クエン酸水溶液で洗浄した。有機層を回収し、Ｎａ２ＳＯ４上で乾燥させ、蒸発させた。残渣をカラムクロマトグラフィー（シリカゲル、０～３０％のＥｔＯＡｃ／ｎ－ヘキサン）で精製し、粗生成物を得た。粗生成物をさらに分取ＨＰＬＣ（８０％ＡＣＮ，２０％Ｈ２Ｏ）で精製し、３４（３２０ｍｇ，収率１１％，２段階）を白色粉末として得た。1H-NMR (CD
Cl3, 500 MHz), δ(ppm): 7.51 (d, J= 7.0 Hz, 2H), 7.17 (d, J= 7.0 Hz, 2H), 7.06 (d, J= 16.0 Hz, 1H), 6.99 (d, J= 16.0 Hz, 1H), 6.66 (s, 2H), 6.41 (s, 1H), 6.36 (brs, NH, 1H), 5.02 (brs, NH, 1H), 4.33 (s, 2H), 3.91 (t, J= 7.5 Hz, 1H), 3.83 (s, 6H), 3.65 (s, 2H), 2.17 (s, 1H) 1.44 (s, 9H), 0.97 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H). Mass found [M - Boc + H]+ = 444.3; [M + H]+= 544.3, [M + Na]+ = 566.3。 (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (34)
To a stirred solution of compound 32 (1469 mg, 5.6 mmol) in dry CH 2 Cl 2 (30 ml) was added triethylamine (1966 ul, 14.1 mmol), followed by dropwise addition of 4-nitrophenyl chloroformate solution (1251 mg, 6.2 mmol, in 30 mL CH 2 Cl 2 ) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for another 4 h, the solvent was removed under vacuum to give crude intermediate 33, which was mixed with pterostilbene (1446 mg, 5.6 mmol) and DMAP (1379 mg, 11.3 mmol) in ACN (30 ml). The resulting mixture was heated to 50° C. and reacted for 1 h. After reaction, the solvent was evaporated. The residue was taken up in EA and washed with saturated aqueous citric acid. The organic layer was collected, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography (silica gel, 0-30% EtOAc/n-hexane) to give the crude product. The crude product was further purified by preparative HPLC (80% ACN, 20% H 2 O) to give 34 (320 mg, 11% yield, 2 steps) as a white powder. 1 H-NMR (CD
Cl3 , 500 MHz), δ(ppm): 7.51 (d, J= 7.0 Hz, 2H), 7.17 (d, J= 7.0 Hz, 2H), 7.06 (d, J= 16.0 Hz, 1H), 6.99 (d, J= 16.0 Hz, 1H), 6.66 (s, 2H), 6.41 (s, 1H), 6.36 (brs, NH, 1H), 5.02 (brs, NH, 1H), 4.33 (s, 2H), 3.91 (t, J= 7.5 Hz, 1H), 3.83 (s, 6H), 3.65 (s, 2H), 2.17 (s, 1H) 1.44 (s, 9H), 0.97 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H). Mass found [M - Boc + H] + = 444.3; [M + H] + = 544.3, [M + Na] + = 566.3.

（Ｅ）－２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）アミノ）エチル ２－アミノ－３－メチルブタノエート塩酸塩（９）
５０ｍＬ丸ビンフラスコに化合物３４（３２０ｍｇ，０．６ｍｍｏｌ）と１，４－ジオキサン中の４Ｍ ＨＣｌ（２．９５ｍＬ）を添加した。得られた混合物を室温で３時間撹拌した。溶媒を減圧下で除去した後、凍結乾燥し、目的生成物の化合物９を白色粉末として得た（２４９ｍｇ，８８％）。1H-NMR (d6-DMSO, 500 MHz), δ(ppm): 8.80 (t, J= 5.0 Hz, NH, 1H), 8.22 (brs, NH2, HCl, 3H), 7.63 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 16.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.15 (d, J= 16.0 Hz, 1H), 6.76 (d, J= 2.0 Hz, 2H), 6.41 (s, 1H), 4.30-4.27 (m, 1H), 4.24-4.20 (m, 1H), 3.76 (s, 6H), 3.64-3.60 (m, 3H), 2.10-2.06 (m, 1H), 0.95-0.90 (m, 6H); 13C-NMR (d6-DMSO, 125 MHz), δ(ppm): 168.64, 161.13, 153.35, 150.49, 139.37, 135.53, 129.37, 128.26, 128.04, 121.92, 105.00, 100.44, 67.38, 57.93, 55.69, 38.01, 30.11, 18.60, 18.37; Mass
found [M + H]+ = 444.3; [M + Na]+ = 466.3。 (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl 2-amino-3-methylbutanoate hydrochloride (9)
To a 50 mL round bottle flask was added compound 34 (320 mg, 0.6 mmol) and 4 M HCl in 1,4-dioxane (2.95 mL). The resulting mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure, followed by lyophilization to give the desired product compound 9 as a white powder (249 mg, 88%). 1H -NMR (d6-DMSO, 500 MHz), δ(ppm): 8.80 (t, J= 5.0 Hz, NH, 1H), 8.22 (brs, NH2 , HCl, 3H), 7.63 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 16.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.15 (d, J= 16.0 Hz, 1H), 6.76 (d, J= 2.0 Hz, 2H), 6.41 (s, 1H), 4.30-4.27 (m, 1H), 4.24-4.20 (m, 1H), 3.76 (s, 6H), 3.64-3.60 (m, 3H), 2.10-2.06 (m, 1H), 0.95-0.90 (m, 6H); 13C -NMR (d6-DMSO, 125 MHz), δ(ppm): 168.64, 161.13, 153.35, 150.49, 139.37, 135.53, 129.37, 128.26, 128.04, 121.92, 105.00, 100.44, 67.38, 57.93, 55.69, 38.01, 30.11, 18.60, 18.37; Mass
Found [M+H] + = 444.3; [M+Na] + = 466.3.

１－２－９．目的化合物１０の合成
スキーム９において、化合物１０の合成について記載した。Ｂｏｃ－Ｖａｌ－ＯＨ（１ｃ）のカルボン酸をＮ－ヒドロキシスクシンイミド（ＮＨＳ）およびジシクロヘキシルカルボジイミド（ＤＣＣ）で活性化すると、アミノ基を介してシステアミンが共役し、夾雑アミド３５が得られた。化合物３５をｐ－ニトロフェニルクロロホルメートと反応させて対応するｐ－ニトロフェニルチオカーボネート３６を得て、これをさらなる精製はせずにプテロスチルベンと反応させて夾雑チオカーボネート３７を得た。その後、Ｂｏｃ基を脱保護することにより、目的化合物１０を得た。 1-2-9. Synthesis of target compound 10 In Scheme 9, the synthesis of compound 10 was described. The carboxylic acid of Boc-Val-OH (1c) was activated with N-hydroxysuccinimide (NHS) and dicyclohexylcarbodiimide (DCC) to conjugate cysteamine via the amino group to give impurity amide 35. Compound 35 was reacted with p-nitrophenyl chloroformate to give the corresponding p-nitrophenyl thiocarbonate 36, which was reacted with pterostilbene without further purification to give impurity thiocarbonate 37. The target compound 10 was then obtained by deprotecting the Boc group.

スキーム９：化合物１０の合成 Scheme 9: Synthesis of compound 10

試薬および条件：（ａ）１．ＮＨＳ，ＤＣＣ，ＴＨＦ，２４時間；２．ＤＩＰＥＡ，ＣＨ２Ｃｌ２，２４時間；（ｂ）ＤＩＰＥＡ，ＣＨ２Ｃｌ２，０℃；（ｃ）ＤＭＡＰ，ＡＣＮ，５０℃，２時間；（ｄ）１，４－ジオキサン中４Ｍ ＨＣｌ，ＣＨ２Ｃｌ２。 Reagents and conditions: (a) 1. NHS, DCC, THF, 24 h; 2. DIPEA, CH 2 Cl 2 , 24 h; (b) DIPEA, CH 2 Cl 2 , 0° C.; (c) DMAP, ACN, 50° C., 2 h; (d) 4M HCl in 1,4-dioxane, CH 2 Cl 2 .

ｔｅｒｔ－ブチル（１－（（２－メルカプトエチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（３５）
Ｂｏｃ－Ｖａｌ－ＯＨ １ｃ（３．２３ｇ，１４．９ｍｍｏｌ）のＴＨＦ（１６ｍＬ）中の溶液に、ＮＨＳ（１．７２ｇ，１５．０ｍｍｏｌ）およびＤＣＣ（３．１ｇ，１５．０ｍｍｏｌ）を添加した。反応混合物を室温で２４時間撹拌し、濾過した。濾液の溶媒を蒸発させ、残渣をＣＨ２Ｃｌ２（１２ｍＬ）に取り込み、次にＤＩＰＥＡ（５．７ｇ，４４．２ｍｍｏｌ）およびシステアミン塩酸塩（１．２３ｇ，１５．９ｍｍｏｌ）を加え、反応混合物を２４時間撹拌した。水（５ｍＬ）を加え、反応混合物をＥＡ（３×２０ｍＬ）で抽出した。合わせた有機層を１Ｎ ＨＣｌ（２×１０ｍＬ）およびブライン（１０ｍＬ）で洗浄した。有機相をＭｇＳＯ４上で乾燥し、蒸発させ、残渣をカラムクロマトグラフィー（シリカゲル、ｎ－ヘキサン／ＥｔＯＡｃ、（４：１、ｖ／ｖ））で精製して３５（１．６７ｇ、収率４１％）を白色固体として得た。1H-NMR (500 MHz, CDCl3), δ (ppm): 6.41 (s, 1H), 5.05 (s, 1H), 3.88-3.85 (m, 1H), 3.49-3.42 (m, 2H), 2.69-2.65 (m, 2H), 2.17-2.15 (m, 1H) 1.45 (s, 9H), 0.96 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H)。 tert-Butyl (1-((2-mercaptoethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (35)
To a solution of Boc-Val-OH 1c (3.23 g, 14.9 mmol) in THF (16 mL) was added NHS (1.72 g, 15.0 mmol) and DCC (3.1 g, 15.0 mmol). The reaction mixture was stirred at room temperature for 24 h and filtered. The filtrate's solvent was evaporated and the residue was taken up in CH 2 Cl 2 (12 mL), then DIPEA (5.7 g, 44.2 mmol) and cysteamine hydrochloride (1.23 g, 15.9 mmol) were added and the reaction mixture was stirred for 24 h. Water (5 mL) was added and the reaction mixture was extracted with EA (3×20 mL). The combined organic layers were washed with 1N HCl (2×10 mL) and brine (10 mL). The organic phase was dried over MgSO4 , evaporated and the residue was purified by column chromatography (silica gel, n-hexane/EtOAc, (4:1, v/v)) to give 35 (1.67 g, 41% yield) as a white solid. 1H -NMR (500 MHz, CDCl3 ), δ (ppm): 6.41 (s, 1H), 5.05 (s, 1H), 3.88-3.85 (m, 1H), 3.49-3.42 (m, 2H), 2.69-2.65 (m, 2H), 2.17-2.15 (m, 1H) 1.45 (s, 9H), 0.96 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H).

ｔｅｒｔ－ブチル（Ｅ）－（１－（（２－（（（４－（３，５－ジメトキシスチリル）フェノキシ）カルボニル）チオ）エチル）アミノ）－３－メチル－１－オキソブタン－２－イル）カルバメート（３７）
脱水ＣＨ２Ｃｌ２（４０ｍｌ）中の化合物３５（１．２６ｇ，４．６ｍｍｏｌ）の撹拌溶液にＤＩＰＥＡ（１．７８ｇ，１３．８ｍｍｏｌ）を加え、次に１０ｍＬ ＣＨ２Ｃｌ
２中の４－ニトロフェニルクロロホルメート溶液（１．０２ｇ，５．１ｍｍｏｌ）を０℃で滴下して加えた。反応混合物を０℃で１５分間撹拌した後、室温に温めた。室温でさらに４時間撹拌した後、溶媒を真空下で除去して粗中間体３６を得て、これをＡＣＮ（３０ｍｌ）中でプテロスチルベン（１．１９ｇ，４．７ｍｍｏｌ）およびＤＭＡＰ（１．１３ｇ，９．３ｍｍｏｌ）と混合した。得られた混合物を５０℃に２時間加熱した。反応後、溶媒を真空下で除去した。残渣をカラムクロマトグラフィー（ＥＡ／ｎ－ヘキサン＝１／５（Ｖ／Ｖ））で精製し、粗生成物を得た。粗生成物をさらに分取ＨＰＬＣ（８０％ＡＣＮ，２０％Ｈ２Ｏ）で精製し、目的化合物３７（１．４６ｇ，収率５６％）を白色粉末として得た。1H-NMR (CDCl3, 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.15 (d, J=
8.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.5 Hz, 2H), 6.41 (t, J= 2.5Hz, 1H), 6.38 (brs, NH), 5.00 (brs, NH), 3.98-3.85 (m,
1H), 3.82 (s, 6H), 3.65-3.54 (m, 2H), 3.13-3.07 (m, 2H), 2.17-2.16 (m, 1H), 1.48 (s, 9H), 0.90 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H); Mass found [M - Boc + H]+ = 460.2; [M + H]+ = 560.3; [M + Na]+ = 582.3。 tert-Butyl (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)thio)ethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (37)
To a stirred solution of compound 35 (1.26 g, 4.6 mmol) in dry CH 2 Cl 2 (40 mL) was added DIPEA (1.78 g, 13.8 mmol), followed by 10 mL CH 2 Cl 2 .
A solution of 4-nitrophenyl chloroformate (1.02 g, 5.1 mmol) in 2 was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then warmed to room temperature. After stirring at room temperature for another 4 h, the solvent was removed under vacuum to give crude intermediate 36, which was mixed with pterostilbene (1.19 g, 4.7 mmol) and DMAP (1.13 g, 9.3 mmol) in ACN (30 ml). The resulting mixture was heated to 50° C. for 2 h. After the reaction, the solvent was removed under vacuum. The residue was purified by column chromatography (EA/n-hexane=1/5 (V/V)) to give the crude product. The crude product was further purified by preparative HPLC (80% ACN, 20% H 2 O) to give the target compound 37 (1.46 g, 56% yield) as a white powder. 1H -NMR ( CDCl3 , 500 MHz), δ(ppm): 7.51 (d, J= 8.0 Hz, 2H), 7.15 (d, J=
8.0 Hz, 2H), 7.05 (d, J= 16.5 Hz, 1H), 6.99 (d, J= 16.5 Hz, 1H), 6.66 (d, J= 2.5 Hz, 2H), 6.41 (t, J= 2.5Hz, 1H), 6.38 (brs, NH), 5.00 (brs, NH), 3.98-3.85 (m,
1H), 3.82 (s, 6H), 3.65-3.54 (m, 2H), 3.13-3.07 (m, 2H), 2.17-2.16 (m, 1H), 1.48 (s, 9H), 0.90 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H); Mass found [M - Boc + H] + = 460.2; [M + H] + = 560.3; [M + Na] + = 582.3.

（Ｅ）－Ｓ－（２－（２－アミノ－３－メチルブタンアミド）エチル）Ｏ－（４－（３，５－ジメトキシスチリル）フェニル）カルボノチオエート塩酸塩（１０）
ＤＣＭ（１５ｍＬ）中の化合物３７（８０５ｍｇ，１．４ｍｍｏｌ）の撹拌溶液に１，４－ジオキサン（７．２０ｍＬ）中の４Ｍ ＨＣｌを加え、混合物を室温で３時間撹拌した。その後、反応溶液を蒸発させ、分取ＨＰＬＣ精製に供した（バッファーとしてＴＦＡ、詳細なグラジエント溶出は下記情報を参照のこと）。その後、水性画分を濃塩酸数滴で処理し、凍結乾燥して化合物１０（６４７ｍｇ，収率９１％）を白色固体として得た。1H-NMR (CD3OD, 500 MHz), δ(ppm): 7.57 (d, J= 9.0 Hz, 2H), 7.15-7.12 (m, 3H), 7.07
(d, J = 16.5 Hz, 1H), 6.70 (d, J = 2.0 Hz, 2H), 6.40 (s, 1H), 3.80 (s, 6H), 3.68-3.62 (m, 2H), 3.52-3.46 (m, 1H), 3.17-3.10 (m, 2H), 2.22-2.18 (m, 1H), 1.08 (d, J = 6.5 Hz, 3H), 1.06 (d, J= 6.5 Hz, 3H); 13C-NMR (CD3OD, 125 MHz), δ(ppm): 169.66, 168.37, 161.13, 150.53, 139.16, 135.69, 129.09, 127.38, 127.23, 121.15, 104.25, 99.66, 58.48, 54.42, 38.55, 30.22, 30.05, 17.52, 16.55; Mass found [M - HCl + H]+ = 459.2; [2M - 2HCl + H]+= 917.3。 (E) -S-(2-(2-amino-3-methylbutanamido)ethyl)O-(4-(3,5-dimethoxystyryl)phenyl)carbonothioate hydrochloride (10)
To a stirred solution of compound 37 (805 mg, 1.4 mmol) in DCM (15 mL) was added 4M HCl in 1,4-dioxane (7.20 mL) and the mixture was stirred at room temperature for 3 h. The reaction solution was then evaporated and subjected to preparative HPLC purification (TFA as buffer, detailed gradient elution see information below). The aqueous fraction was then treated with a few drops of concentrated hydrochloric acid and lyophilized to give compound 10 (647 mg, 91% yield) as a white solid. 1 H-NMR (CD 3 OD, 500 MHz), δ(ppm): 7.57 (d, J= 9.0 Hz, 2H), 7.15-7.12 (m, 3H), 7.07
(d, J = 16.5 Hz, 1H), 6.70 (d, J = 2.0 Hz, 2H), 6.40 (s, 1H), 3.80 (s, 6H), 3.68-3.62 (m, 2H), 3.52-3.46 (m, 1H), 3.17-3.10 (m, 2H), 2.22-2.18 (m, 1H), 1.08 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 6.5 Hz, 3H); 13C -NMR ( CD3OD , 125MHz), δ(ppm): 169.66, 168.37, 161.13, 150.53, 139.16, 135.69, 129.09, 127.38, 127.23, 121.15, 104.25, 99.66, 58.48, 54.42, 38.55, 30.22, 30.05, 17.52, 16.55; Mass found [M - HCl + H] + = 459.2; [2M - 2HCl + H] + = 917.3.

カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３ Ｃ１８，５ｕｍ，３０＊２５０ｍｍ
流量：３８ｍｌ／分
溶媒Ａ：Ｈ２Ｏ中１０％ＡＣＮ＋０．１％ＴＦＡ
溶媒Ｂ：Ｈ２Ｏ中９０％ＡＣＮ＋０．１％ＴＦＡ
グラジエント： Column: Inertsil ODS-3 C18, 5um, 30*250mm
Flow rate: 38 ml/min Solvent A: 10% ACN + 0.1% TFA in H2O
Solvent B: 90% ACN + 0.1% TFA in H2O
Gradient:

２．インビボ試験における目的化合物の抗ＮＡＦＬＤおよび抗ＮＡＳＨについて
２－１．原料および方法
動物および実験プロトコル：４週齢の雄のＣ５７ＢＬ／６マウスを実験動物センター（台湾、中国）から購入し、健康研究機関（台湾、中国）の機関動物管理および使用委員会が提供する手順およびガイドラインの下で維持した。ステンレス製のケージで、ペレットフードおよび水に自由にアクセスできるように維持し、温度２１±２℃、１２時間の明暗サイクルで飼育した。すべての実験は、中国医科大学（中国、台湾）の動物実験委員会の下で監督され、プロトコル番号（ＣＭＵＩＡＣＵＣ－２０２０－１１７）を付与された。 2. Anti-NAFLD and anti-NASH of the target compound in in vivo test 2-1. Materials and methods Animals and experimental protocol: 4-week-old male C57BL/6 mice were purchased from the Laboratory Animal Center (Taiwan, China) and maintained under the procedures and guidelines provided by the Institutional Animal Care and Use Committee of the Health Research Institute (Taiwan, China). They were kept in stainless steel cages with free access to pellet food and water, and kept at a temperature of 21 ± 2 °C and a 12-hour light-dark cycle. All experiments were supervised under the Animal Care and Use Committee of China Medical University (Taiwan, China) and were given the protocol number (CMUIACUC-2020-117).

前記合成目的化合物（５ａ，５ｂ，５ｃ，５ｄ，５ｅ，５ｆ，５ｇ，５ｈ，５ｊ，５ｍ，５ｐ，５ｔ，５ｖ，５ｗ，６ａ，６ｂ，６ｇ，７ｃ，７ｅ）をＰＧ／ＴＰＳＧ（１：１）に溶解させた。マウスにＭＣＤ食を１４日間投与した後、対照としてＰＧ／ＴＰＳＧ（１：１）、およびすべての化合物の１００ｍｇ／ｋｇを１日１回、週５回、４２日間経口投与した。マウスを無作為に５群に分け、以下のように処理した：（１）ＭＣＤ食＋ＰＧ／ＴＰＳＧ（２）ＭＣＤ食＋全化合物１００ｍｇ／ｋｇ。２８日後、血漿ＡＬＴおよび血漿ＡＳＴ濃度を測定するための採血と、Ｈ＆Ｅ染色用の肝臓サンプル採取とのために、動物を犠牲にした。 The synthetic target compounds (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5j, 5m, 5p, 5t, 5v, 5w, 6a, 6b, 6g, 7c, 7e) were dissolved in PG/TPSG (1:1). Mice were fed the MCD diet for 14 days, followed by oral administration of PG/TPSG (1:1) as a control and 100 mg/kg of all compounds once a day, 5 times a week, for 42 days. Mice were randomly divided into 5 groups and treated as follows: (1) MCD diet + PG/TPSG (2) MCD diet + 100 mg/kg of all compounds. After 28 days, animals were sacrificed for blood sampling to measure plasma ALT and plasma AST concentrations, and liver samples for H&E staining.

マウスにＭＣＤ食を１４日間投与した後、ＤＤＷ、並びに７５、１００、および１５０ｍｇ／ｋｇの化合物５ｃを１日１回、週５回、４２日間経口投与した。マウスを無作為に５群に分け、以下のように処理した：（１）シャム群（非ＭＣＤ食）（２）ＭＣＤ食（３）ＭＣＤ食＋７５ｍｇ／ｋｇの化合物５ｃ（４）ＭＣＤ食＋１００ｍｇ／ｋｇの化合物５ｃ（５）ＭＣＤ食＋１５０ｍｇ／ｋｇの化合物５ｃ。２８日後、血漿ＡＬＴ濃度および血漿ＡＳＴ濃度を測定するための採血と、Ｈ＆Ｅ染色用の肝臓サンプル採取とのために、動物を犠牲にした。 Mice were fed the MCD diet for 14 days, followed by oral administration of DDW and 75, 100, and 150 mg/kg of compound 5c once a day, 5 times a week, for 42 days. Mice were randomly divided into 5 groups and treated as follows: (1) Sham group (non-MCD diet), (2) MCD diet, (3) MCD diet + 75 mg/kg of compound 5c, (4) MCD diet + 100 mg/kg of compound 5c, and (5) MCD diet + 150 mg/kg of compound 5c. After 28 days, animals were sacrificed for blood collection to measure plasma ALT and AST concentrations, and liver samples for H&E staining.

２－２．結果および考察
ＭＣＤ食により誘発される肝脂肪症の発症に対する全化合物（５ａ、５ｂ、５ｃ、５ｄ、５ｅ、５ｆ、５ｇ、５ｈ、５ｊ、５ｍ、５ｐ、５ｔ、５ｖ、５ｗ、６ａ、６ｂ、６ｇ、７ｃ、７ｅ）の影響を測定するために組織学研究を行った。Ｈ＆Ｅ染色の結果、ＭＣＤ食の摂取は、肝脂肪症、肝細胞の損傷、並びに炎症細胞の浸潤、肥大化および線維化を有意に誘発することが示された。化合物５ａ、５ｂ、５ｃ、５ｆ、５ｔ、６ｇ、７ｃ、７ｅ、５ｗ、５ｇ、５ｄ、５ｅ、５ｊ、５ｍ、５ｐ、６ａ、６ｂによる処理によって、脂肪症、炎症、肥大化、線維化が減少し、ＭＣＤ食誘発の脂肪性肝炎を抑制した（表１）。 2-2. Results and Discussion Histological studies were performed to determine the effect of all compounds (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5j, 5m, 5p, 5t, 5v, 5w, 6a, 6b, 6g, 7c, 7e) on the development of hepatic steatosis induced by MCD diet. H&E staining results showed that MCD diet intake significantly induced hepatic steatosis, hepatocyte injury, and inflammatory cell infiltration, hypertrophy, and fibrosis. Treatment with compounds 5a, 5b, 5c, 5f, 5t, 6g, 7c, 7e, 5w, 5g, 5d, 5e, 5j, 5m, 5p, 6a, and 6b reduced steatosis, inflammation, hypertrophy, and fibrosis, and suppressed MCD diet-induced steatohepatitis (Table 1).

血清中のＡＳＴおよびＡＬＴの濃度は、肝障害の指標となる。表２に示すように、ＭＣＤ食を与えたマウスのＡＳＴおよびＡＬＴの血清濃度は、普通食を与えたマウスに比べ、有意に上昇した。化合物５ｃ、５ａ、５ｂ、５ｆ、５ｈ、５ｄ、５ｍおよび５ｐは、用量依存的にＡＳＴおよびＡＬＴの血清濃度を有意に抑制した。 The concentrations of AST and ALT in serum are indicators of liver damage. As shown in Table 2, the serum concentrations of AST and ALT in mice fed the MCD diet were significantly increased compared to mice fed a normal diet. Compounds 5c, 5a, 5b, 5f, 5h, 5d, 5m and 5p significantly inhibited the serum concentrations of AST and ALT in a dose-dependent manner.

化合物５ｃは最も有望であり、さらなる評価のために選択された。ＭＣＤ食によって誘発される肝脂肪症の発症に対する化合物５ｃの効果を測定するために、組織学的研究を行った。Ｈ－Ｅ染色の結果、ＭＣＤ食の給与は、肝脂肪症、肝細胞の損傷、並びに炎症細胞の浸潤、肥大化および線維化を有意に誘発した。化合物５ｃによる処理によって、脂肪症、炎症、肥大化、および線維化が減少し、ＭＣＤ食誘発の脂肪性肝炎を抑制した（図１、表３）。 Compound 5c was the most promising and was selected for further evaluation. Histological studies were performed to measure the effect of compound 5c on the development of hepatic steatosis induced by the MCD diet. H-E staining showed that feeding the MCD diet significantly induced hepatic steatosis, hepatocyte damage, as well as inflammatory cell infiltration, hypertrophy, and fibrosis. Treatment with compound 5c reduced steatosis, inflammation, hypertrophy, and fibrosis, and inhibited MCD diet-induced steatohepatitis (Figure 1, Table 3).

血清中のＡＳＴおよびＡＬＴの濃度は、肝障害の指標となる。表４に示すように、ＭＣＤ食を与えたマウスのＡＳＴおよびＡＬＴの血清濃度は、普通食を与えたマウスに比べ、有意に上昇した。化合物５ｃは、ＡＳＴおよびＡＬＴの血清濃度を用量依存的に有意に抑制した。 The concentrations of AST and ALT in serum are indicators of liver damage. As shown in Table 4, the serum concentrations of AST and ALT in mice fed the MCD diet were significantly increased compared to mice fed a normal diet. Compound 5c significantly inhibited the serum concentrations of AST and ALT in a dose-dependent manner.

３．目的化合物の安定性および溶解性
３－１．化合物５ａ、５ｃ、５ｍ、５ｖ、５ｗ、６ａおよび６ｂのｐＨ１．２溶液（酵素のないＵＳＰ胃液）におけるインビトロ安定性
３－１－１．原料および方法
原料：本発明の目的化合物５ａ、５ｃ、５ｍ、５ｖ、５ｗ、６ａおよび６ｂ。 3. Stability and solubility of the target compounds 3-1. In vitro stability of compounds 5a, 5c, 5m, 5v, 5w, 6a and 6b in pH 1.2 solution (USP gastric fluid without enzymes) 3-1-1. Materials and methods Materials: target compounds 5a, 5c, 5m, 5v, 5w, 6a and 6b of the present invention.

試薬：ｐＨ＝１．２溶液 ＮａＣｌ ２．０ｇをＨ２Ｏ ８００ｍＬに溶解させ、ｃｏｎｃ．ＨＣｌ ７．０ｍＬを加えた。混合物を撹拌し、２ＮのＮａＯＨと、２Ｎの、ｃｏｎｃ．ＨＣｌおよびＨ２Ｏにより１０倍希釈したｃｏｎｃ．ＨＣｌ、とにより、ｐＨ１．２に調整し、１０００ｍＬとした。 Reagents: pH=1.2 solution 2.0 g NaCl was dissolved in 800 mL H2O and 7.0 mL conc. HCl was added. The mixture was stirred and adjusted to pH 1.2 with 2N NaOH, 2N conc. HCl and conc. HCl diluted 10 times with H2O , and made up to 1000 mL.

インビトロ実験：化合物５ａ、５ｃ、５ｍ、５ｖ、５ｗ、６ａおよび６ｂを別々にｐＨ１．２の溶液で３７℃、６時間インキュベートした。サンプル採取：０時間，０．１７時間，０．５時間，１時間，２時間，４時間および６時間後に、インキュベーション混合物から１００ｍＬの分量を採取し、氷冷アセトニトリル１００μＬおよび１μｍの内部標準を含む遠心管に入れ、反応を停止させた。試料を１５０００ｒｐｍで１０分間遠心分離し、上清をＨＰＬＣシステムに注入した。 In vitro experiments: Compounds 5a, 5c, 5m, 5v, 5w, 6a and 6b were separately incubated in pH 1.2 solution at 37°C for 6 hours. Sample collection: After 0, 0.17, 0.5, 1, 2, 4 and 6 hours, 100 mL aliquots were taken from the incubation mixture and placed in centrifuge tubes containing 100 μL ice-cold acetonitrile and 1 μM internal standard to stop the reaction. Samples were centrifuged at 15000 rpm for 10 minutes and the supernatant was injected into the HPLC system.

ＨＰＬＣの方法：ＨＰＬＣ：Ｗａｔｅｒｓ １５２５ Ｂｉｎａｒｙ ＨＰＬＣ Ｐｕｍｐ；Ｗａｔｅｒｓ ２７０７ Ａｕｔｏｓａｍｐｌｅｒ；Ｗａｔｅｒｓ ２４８７ Ｄｕａｌ λ Ａｂｓｏｒｂａｎｃｅ Ｄｅｔｅｃｔｏｒ；カラム：ＸＢｒｉｄｇｅ Ｓｈｉｅｌｄ ＲＰ１８，５μｍ，４．６×５０ｍｍカラム；ＵＶ検出器：３０５ｎｍ；温度：室温；実行時間：１５．０分；移動相：Ａ：Ｈ２Ｏ中０．１％ＦＡ；Ｂ：アセトニトリル。 HPLC Method: HPLC: Waters 1525 Binary HPLC Pump; Waters 2707 Autosampler; Waters 2487 Dual λ Absorbance Detector; Column: XBridge Shield RP18, 5 μm, 4.6×50 mm column; UV detector: 305 nm; Temperature: room temperature; Run time: 15.0 min; Mobile phase: A: 0.1% FA in H 2 O; B: acetonitrile.

３－１－２．結果および考察
試験した化合物のレベルを表５で比較した。その結果、これらの試験化合物はｐＨ＝１．２溶液中で比較的安定であることを示した。６時間培養した結果、化合物５ａ，５ｃ，５ｍ，５ｗ，６ａ，および６ｂはｐＨ＝１．２の溶液中に９０％超残存していた。一方、化合物５ｖは８４．８％のみ残存した。 3-1-2. Results and Discussion The levels of the tested compounds are compared in Table 5. The results showed that the test compounds were relatively stable in pH=1.2 solution. After 6 hours of incubation, more than 90% of compounds 5a, 5c, 5m, 5w, 6a, and 6b remained in the pH=1.2 solution. Meanwhile, only 84.8% of compound 5v remained.

結論として、インビトロ試験において、これらの目的化合物は（酵素を含まない）胃液に対して比較的安定であることが示された。時間依存の分解は観察されなかった。 In conclusion, in vitro studies have shown that these compounds are relatively stable in (enzyme-free) gastric fluids. No time-dependent degradation was observed.

３－２．化合物５ｃのＨ２Ｏへの溶解度
３－２－１．原料および方法
化合物５ｃの濃度はＨ２Ｏで４０ｍｇ／ｍＬとした。超音波処理およびボルテックスをそれぞれ３０分間行った後、チューブを２５℃で静置した。サンプリング時点（１、３、６、２４時間）で、チューブを１５，０００ｒｐｍで１０分間遠心分離し、上清を回収し
てアセトニトリルで適切に希釈した。サンプルはＨＰＬＣで定量した。 3-2. Solubility of Compound 5c in H 2 O 3-2-1. Materials and Methods The concentration of Compound 5c was 40 mg/mL in H 2 O. After ultrasonication and vortexing for 30 minutes each, the tube was left at 25°C. At the sampling time points (1, 3, 6, and 24 hours), the tube was centrifuged at 15,000 rpm for 10 minutes, and the supernatant was collected and appropriately diluted with acetonitrile. The samples were quantified by HPLC.

ＨＰＬＣの方法：カラム：ＸＢｒｉｄｇｅ Ｓｈｉｅｌｄ ＲＰ１８，５μｍ，４．６×５０ｍｍ；ＵＶ検出器：３０５ｎｍ；温度：室温；注入量：１０μＬ；実行時間：１５．０分；移動相：Ａ：Ｈ２Ｏ中０．１％ＦＡ；Ｂ：アセトニトリル。 HPLC method: Column: XBridge Shield RP18, 5 μm, 4.6×50 mm; UV detector: 305 nm; Temperature: room temperature; Injection volume: 10 μL; Run time: 15.0 min; Mobile phase: A: 0.1% FA in H 2 O; B: acetonitrile.

３－２－２．結果および考察
表６および図２に示すように、２４時間後の２５℃におけるＨ２Ｏへの化合物５ｃの溶解度は、３４ｍｇ／ｍＬより高い。米国薬局方の基準では、化合物５ｃは水溶性物質と呼ばれ得る。 3-2-2. Results and Discussion As shown in Table 6 and Figure 2, the solubility of compound 5c in H 2 O at 25°C after 24 hours is higher than 34 mg/mL. According to the United States Pharmacopoeia standard, compound 5c can be called a water-soluble substance.

４．結論
本発明では、水溶性プテロスチルベンアミノ酸含有炭酸塩の一連の新規類縁体を合成した。これらの化合物はｐＨ＝１．２（酵素のない胃液のｐＨ値）で安定であり、抗ＮＡＳＨ活性が検討されている。合成した化合物の多くは、抗ＮＡＳＨ／ＮＡＦＬＤ活性を示した（表１，２参照のこと）。その中で、化合物５ｃが最も有望であり、さらなる評価に選ばれた。その結果、化合物５ｃ（代表化合物）が有意な抗ＮＡＳＨ／ＮＡＦＬＤ活性を示すことが明らかとなった（図１、表３、表４）。 4. Conclusion In the present invention, a series of novel analogues of water-soluble pterostilbene amino acid-containing carbonate salts were synthesized. These compounds are stable at pH=1.2 (pH value of gastric juice without enzymes), and anti-NASH activity has been investigated. Many of the synthesized compounds showed anti-NASH/NAFLD activity (see Tables 1 and 2). Among them, compound 5c was the most promising and was selected for further evaluation. As a result, it was revealed that compound 5c (representative compound) showed significant anti-NASH/NAFLD activity (Figure 1, Tables 3 and 4).

本発明のプテロスチルベンアミノ酸含有炭酸塩類縁体の新規の一連の化学構造は、水溶性で、安定であり、インビボでのＮＡＦＬＤ／ＮＡＳＨの治療に有効であるため、ＮＡＦＬＤ／ＮＡＳＨの治療のための新規の薬剤として開発される可能性を有する。 The novel series of chemical structures of the pterostilbene amino acid-containing carbonate analogs of the present invention are water-soluble, stable, and effective in treating NAFLD/NASH in vivo, and therefore have the potential to be developed as novel drugs for the treatment of NAFLD/NASH.

参考文献
1.FDA. Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry. FDA DRAFT GUIDANCE. 2019.
2.Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018;53(3):362-76.
3.Goldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, et al. Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure
on the Waitlist for Liver Transplantation. Gastroenterology. 2017;152(5):1090-9
e1.
4.Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84.
5.Thiagarajan P, Aithal GP. Drug Development for Nonalcoholic Fatty Liver Disease: Landscape and Challenges. J Clin Exp Hepatol. 2019;9(4):515-21.
6.Wu J. [Machanism and intervention of nonalcoholic steatohepatitis-associated fibrosis]. Zhonghua Gan Zang Bing Za Zhi. 2019;27(6):415-9.
7.Kudaravalli P, John S. Nonalcoholic Fatty Liver. StatPearls. Treasure Island (FL)2019.
8.Mathews SE, Kumar RB, Shukla AP. Nonalcoholic steatohepatitis, obesity, and cardiac dysfunction. Curr Opin Endocrinol Diabetes Obes. 2018;25(5):315-20.
9.Fiorucci S, Di Giorgio C, Distrutti E. Obeticholic Acid: An Update of Its Pharmacological Activities in Liver Disorders. Handb Exp Pharmacol. 2019;256:283-95.10.Ma Z, Zhang X, Xu L, Liu D, Di S, Li W, et al. Pterostilbene: Mechanisms of its action as oncostatic agent in cell models and in vivo studies. Pharmacol Res.
2019;145:104265.
11.Akinwumi BC, Bordun KM, Anderson HD. Biological Activities of Stilbenoids. Int J Mol Sci. 2018;19(3).
12.Lange KW, Li S. Resveratrol, pterostilbene, and dementia. Biofactors. 2018;44(1):83-90.
13.Estrela JM, Ortega A, Mena S, Rodriguez ML, Asensi M. Pterostilbene: Biomedical applications. Crit Rev Clin Lab Sci. 2013;50(3):65-78.
14.Aguirre L, Palacios-Ortega S, Fernandez-Quintela A, Hijona E, Bujanda L, Portillo MP. Pterostilbene Reduces Liver Steatosis and Modifies Hepatic Fatty Acid Profile in Obese Rats. Nutrients. 2019;11(5).
15.Gomez-Zorita S, Milton-Laskibar I, Aguirre L, Fernandez-Quintela A, Xiao J, M
PP. Effects of pterostilbene on diabetes, liver steatosis and serum lipids. Curr Med Chem. 2019.
16.Ruiz MJ, Fernandez M, Pico Y, Manes J, Asensi M, Carda C, et al. Dietary administration of high doses of pterostilbene and quercetin to mice is not toxic. J Agric Food Chem. 2009;57(8):3180-6.
17.Coimbra M, Isacchi B, van Bloois L, Torano JS, Ket A, Wu X, et al. Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes. Int J Pharm. 2011;416(2):433-42.
18.Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. 2011;68(3):593-601.
19.Azzolini M, Mattarei A, La Spina M, Fanin M, Chiodarelli G, Romio M, et al. New natural amino acid-bearing prodrugs boost pterostilbene's oral pharmacokinetic and distribution profile. Eur J Pharm Biopharm. 2017;115:149-58.
20.Gonzalez-Alfonso JL, Rodrigo-Frutos D, Belmonte-Reche E, Penalver P, Poveda A, Jimenez-Barbero J, et al. Enzymatic Synthesis of a Novel Pterostilbene alpha-Glucoside by the Combination of Cyclodextrin Glucanotransferase and Amyloglucosidase. Molecules. 2018;23(6). References
1.FDA. Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry. FDA DRAFT GUIDANCE. 2019.
2.Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018;53(3):362-76.
3.Goldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, et al. Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure
on the Waitlist for Liver Transplantation. Gastroenterology. 2017;152(5):1090-9
e1.
4.Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84.
5.Thiagarajan P, Aithal GP. Drug Development for Nonalcoholic Fatty Liver Disease: Landscape and Challenges. J Clin Exp Hepatol. 2019;9(4):515-21.
6.Wu J. [Machanism and intervention of nonalcoholic steatohepatitis-associated fibrosis]. Zhonghua Gan Zang Bing Za Zhi. 2019;27(6):415-9.
7.Kudaravalli P, John S. Nonalcoholic Fatty Liver. StatPearls. Treasure Island (FL)2019.
8.Mathews SE, Kumar RB, Shukla AP. Nonalcoholic steatohepatitis, obesity, and cardiac dysfunction. Curr Opin Endocrinol Diabetes Obes. 2018;25(5):315-20.
9.Fiorucci S, Di Giorgio C, Distrutti E. Obeticholic Acid: An Update of Its Pharmacological Activities in Liver Disorders. Handb Exp Pharmacol. 2019;256:283-95.10.Ma Z, Zhang X, Xu L, Liu D, Di S, Li W, et al. Pterostilbene: Mechanisms of its action as oncostatic agent in cell models and in vivo studies. Pharmacol Res.
2019;145:104265.
11.Akinwumi BC, Bordun KM, Anderson HD. Biological Activities of Stilbenoids. Int J Mol Sci. 2018;19(3).
12.Lange KW, Li S. Resveratrol, pterostilbene, and dementia. Biofactors. 2018;44(1):83-90.
13.Estrela JM, Ortega A, Mena S, Rodriguez ML, Asensi M. Pterostilbene: Biomedical applications. Crit Rev Clin Lab Sci. 2013;50(3):65-78.
14.Aguirre L, Palacios-Ortega S, Fernandez-Quintela A, Hijona E, Bujanda L, Portillo MP. Pterostilbene Reduces Liver Steatosis and Modifies Hepatic Fatty Acid Profile in Obese Rats. Nutrients. 2019;11(5).
15. Gomez-Zorita S, Milton-Laskibar I, Aguirre L, Fernandez-Quintela A, Xiao J, M
PP. Effects of pterostilbene on diabetes, liver steatosis and serum lipids. Curr Med Chem. 2019.
16.Ruiz MJ, Fernandez M, Pico Y, Manes J, Asensi M, Carda C, et al. Dietary administration of high doses of pterostilbene and quercetin to mice is not toxic. J Agric Food Chem. 2009;57(8):3180-6.
17.Coimbra M, Isacchi B, van Bloois L, Torano JS, Ket A, Wu X, et al. Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes. Int J Pharm. 2011;416(2):433-42.
18.Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. 2011;68(3):593-601.
19.Azzolini M, Mattarei A, La Spina M, Fanin M, Chiodarelli G, Romio M, et al. New natural amino acid-bearing prodrugs boost pterostilbene's oral pharmacokinetic and distribution profile. Eur J Pharm Biopharm. 2017;115:149-58.
20.Gonzalez-Alfonso JL, Rodrigo-Frutos D, Belmonte-Reche E, Penalver P, Poveda A, Jimenez-Barbero J, et al. Enzymatic Synthesis of a Novel Pterostilbene alpha-Glucoside by the Combination of Cyclodextrin Glucanotransferase and Amyloglucosidase. Molecules. 2018;23(6).

Claims (15)

以下の式を有する化合物、またはその薬学的に許容される塩：

式中、ｎは１～３であり；
ｍは２～６であり；
Ｑ、ＸおよびＹはそれぞれ独立に、Ｏ、Ｓ、またはＮＨであり；
Ｒａ、ＲｂおよびＲｃは、それぞれ独立に、Ｈ、ハロゲン、Ｃ１～Ｃ６直鎖アルキル、Ｃ１～Ｃ６直鎖アルコキシ、Ｃ３～Ｃ６分岐アルキル、Ｃ３～Ｃ６分岐アルコキシまたはＣ１～Ｃ６フルオロアルコキシであり；
ＲｄおよびＲｅは、それぞれ独立に、Ｈ、ハロゲン、Ｃ１～Ｃ６直鎖アルキル、Ｃ１～Ｃ６直鎖アルコキシ、Ｃ３～Ｃ６分枝アルキル、Ｃ３～Ｃ６分枝アルコキシもしくはＣ１～Ｃ６フルオロアルコキシ、またはＲｄとＲｅとが連結して環状構造を形成し、

となり、式中、ｊは１～３である。 A compound having the formula:

wherein n is 1 to 3;
m is 2 to 6;
Q, X and Y are each independently O, S, or NH;
Ra, Rb and Rc are each independently H, halogen, C1-C6 straight chain alkyl, C1-C6 straight chain alkoxy, C3-C6 branched alkyl, C3-C6 branched alkoxy or C1-C6 fluoroalkoxy;
Rd and Re are each independently H, halogen, C1-C6 linear alkyl, C1-C6 linear alkoxy, C3-C6 branched alkyl, C3-C6 branched alkoxy or C1-C6 fluoroalkoxy, or Rd and Re are linked to form a cyclic structure;

where j is 1 to 3. ＱがＯであり；ＸがＯであり；ＹがＮＨである、請求項１に記載の化合物、またはその薬学的に許容される塩。 The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Q is O; X is O; and Y is NH. ＱがＯであり；ＸがＮＨであり、ＹがＮＨである、請求項１に記載の化合物、またはその薬学的に許容される塩。 The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Q is O; X is NH; and Y is NH. ＱがＯであり；ＸがＯであり；ＹがＯである、請求項１に記載の化合物、またはその薬学的に許容される塩。 The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Q is O; X is O; and Y is O. ＱがＯであり；ＸがＮＨであり；ＹがＯである、請求項１に記載の化合物、またはその薬学的に許容される塩。 The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Q is O; X is NH; and Y is O. ＱがＯであり；ＸがＳであり；ＹがＮＨである、請求項１に記載の化合物、またはその薬学的に許容される塩。 The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Q is O; X is S; and Y is NH. ｍが２であり；ｎが１または２である、請求項１～６のいずれか１項に記載の化合物、またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 6, wherein m is 2; and n is 1 or 2, or a pharma- ceutically acceptable salt thereof. ＲａおよびＲｂがメトキシである、請求項１～６のいずれか１項に記載の化合物、またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein Ra and Rb are methoxy. ＲａおよびＲｂが３，５－ジメトキシである、請求項８に記載の化合物、またはその薬学的に許容される塩。 The compound according to claim 8, or a pharma- ceutically acceptable salt thereof, wherein Ra and Rb are 3,5-dimethoxy. ＲｄがＣ３～Ｃ６分岐アルキルである、請求項１～６のいずれか１項に記載の化合物、またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 6, wherein Rd is a C3-C6 branched alkyl, or a pharma- ceutically acceptable salt thereof. Ｒｄがイソプロピルである、請求項１０に記載の化合物、またはその薬学的に許容される塩。 The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein Rd is isopropyl. ＲｄとＲｅとが連結して環構造を形成し、

となり、式中、ｊは１である、請求項１～６のいずれか１項に記載の化合物、またはその薬学的に許容される塩。 Rd and Re are linked to form a ring structure,

wherein j is 1, or a pharma- ceutically acceptable salt thereof. 前記薬学的に許容される塩が塩酸塩またはニコチン酸塩である、請求項１～６のいずれか１項に記載の化合物、またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein the pharma-ceutically acceptable salt is a hydrochloride or a nicotinate. 対象における非アルコール性脂肪性肝疾患を治療するための医薬組成物であって、請求項１～１３のいずれか１項に記載の化合物、またはその薬学的に許容される塩の前記治療のための治療有効量を含む、医薬組成物。 A pharmaceutical composition for treating non-alcoholic fatty liver disease in a subject, comprising a therapeutically effective amount for said treatment of a compound according to any one of claims 1 to 13, or a pharma- ceutical acceptable salt thereof. 対象における非アルコール性脂肪性肝炎を治療するための医薬組成物であって、請求項１～１３のいずれか１項に記載の化合物、またはその薬学的に許容される塩の前記治療のための治療有効量を含む、医薬組成物。 A pharmaceutical composition for treating non-alcoholic steatohepatitis in a subject, comprising a therapeutically effective amount for said treatment of a compound according to any one of claims 1 to 13, or a pharma- ceutical acceptable salt thereof.
JP2022575390A 2020-06-12 2021-06-08 Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis Active JP7486615B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202063038142P 2020-06-12 2020-06-12
US63/038,142 2020-06-12
PCT/CN2021/098765 WO2021249364A1 (en) 2020-06-12 2021-06-08 Novel analogs of pterostilbene amino acid bearing carbonates for treating a non-alcoholic fatty liver disease and nonalcoholic steatohepatitis

Publications (2)

Publication Number Publication Date
JP2023533661A JP2023533661A (en) 2023-08-04
JP7486615B2 true JP7486615B2 (en) 2024-05-17

Family

ID=78845324

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2022575390A Active JP7486615B2 (en) 2020-06-12 2021-06-08 Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Country Status (9)

Country Link
US (1) US20230234912A1 (en)
EP (1) EP4136063A4 (en)
JP (1) JP7486615B2 (en)
KR (1) KR20230009407A (en)
CN (1) CN115835860A (en)
AU (1) AU2021288365B2 (en)
CA (1) CA3182510A1 (en)
TW (1) TWI826795B (en)
WO (1) WO2021249364A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009522236A (en) 2005-12-29 2009-06-11 イミュファルマ・フランス・エスアー Azaheterocycles for the treatment of malaria or AIDS
WO2014147641A2 (en) 2013-03-21 2014-09-25 Laurus Labs Private Limited Sitagliptin pterostilbene phosphate salt, process for the preparation and pharmaceutical composition thereof
JP2018524389A (en) 2015-07-22 2018-08-30 ジーエヌティー バイオテック アンド メディカルズ コーポレイション PH-sensitive linker for delivering therapeutic agents
JP2019535688A (en) 2016-10-31 2019-12-12 バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Prodrugs of kallikrein inhibitors

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6768008B2 (en) * 2000-04-24 2004-07-27 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2010046926A2 (en) * 2008-10-17 2010-04-29 Aptuit Laurus Pvt Ltd Novel stilbene analogs
WO2011031934A1 (en) * 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
CA2928794C (en) * 2014-01-31 2019-08-13 Daiichi Sankyo Company, Limited Anti-her2 antibody-drug conjugate
WO2017090007A1 (en) * 2015-11-29 2017-06-01 Rao M Surya Compositions and methods for the treatment of urea cycle disorders and hepatic diseases
CN109996541A (en) * 2016-09-07 2019-07-09 普利安特治疗公司 N- acyl amino acid compounds and its application method
US20210371446A1 (en) * 2018-10-16 2021-12-02 President And Fellows Of Harvard College Sirt1 activating compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009522236A (en) 2005-12-29 2009-06-11 イミュファルマ・フランス・エスアー Azaheterocycles for the treatment of malaria or AIDS
WO2014147641A2 (en) 2013-03-21 2014-09-25 Laurus Labs Private Limited Sitagliptin pterostilbene phosphate salt, process for the preparation and pharmaceutical composition thereof
JP2018524389A (en) 2015-07-22 2018-08-30 ジーエヌティー バイオテック アンド メディカルズ コーポレイション PH-sensitive linker for delivering therapeutic agents
JP2019535688A (en) 2016-10-31 2019-12-12 バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Prodrugs of kallikrein inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AZZOLINI, M. et al.，New natural amino acid-bearing prodrugs boost pterostilbene’s oral pharmacokinetic and distribution profile，European Journal of Pharmaceutics and Biopharmaceutics，2017年，115，pp. 149-158

Also Published As

Publication number Publication date
EP4136063A1 (en) 2023-02-22
KR20230009407A (en) 2023-01-17
EP4136063A4 (en) 2023-10-11
WO2021249364A1 (en) 2021-12-16
TW202146374A (en) 2021-12-16
TWI826795B (en) 2023-12-21
US20230234912A1 (en) 2023-07-27
CN115835860A (en) 2023-03-21
AU2021288365B2 (en) 2023-07-06
JP2023533661A (en) 2023-08-04
AU2021288365A1 (en) 2023-02-02
CA3182510A1 (en) 2021-12-16

Similar Documents

Publication Publication Date Title
US20230110295A1 (en) Targeted compositions
ES2315897T3 (en) AMINO ACIDS DERIVED FROM PORPHARMACOS OF PROPOFOL COMPOSITIONS AND USES OF THE SAME.
CN107033087B (en) 1H-indazole-4-amine compounds and use thereof as IDO inhibitors
US6235717B1 (en) Pharmaceutical compounds
US10456405B2 (en) Nitric oxide-releasing prodrug molecule of substituted quinazolines
JP4417551B2 (en) Hemia Stalin analog
CA2885973C (en) Dolastatin-10 derivative, method of producing the same and anticancer drug composition containing the same
US11793881B2 (en) Polyethylene glycol conjugate medicament, preparation method therefor and use thereof
RU2638549C2 (en) Derivative cyclic amine and its pharmaceutical application
JP3947229B2 (en) Depsipeptide and medicine containing the same as an active ingredient
PT92554A (en) PROCESS FOR THE PREPARATION OF RETROVIRAL PROTEASE INHIBITOR PEPTIDE
JP7486615B2 (en) Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
JP2024014933A (en) Glucosamine derivatives for prevention or treatment of joint disorders
CN104587487B (en) A kind of new branched linkers applied to targeting drug delivery system
JP2021508732A (en) Glucosamine derivatives to prevent or treat joint disorders
Nemoto et al. Synthesis of Paclitaxel–BGL Conjugates
JPH0651677B2 (en) Dipeptide derivative, production method and use thereof
CN112218878A (en) NTCP inhibitors
US20150011484A1 (en) Prodrugs of d-gamma-glutamyl-d-tryptophan and d-gamma-glutamyl-l-tryptophan
JPWO2003059870A1 (en) N-substituted sulfonamide derivative and drug for preventing or treating diabetes containing the same
Toth et al. Synthesis and Oral Uptake Studies of Lipidic and Glyco‐Lipidic Conjugates of β‐Lactam Antibiotics
CN103626837A (en) Glycogen phosphorylase inhibitor cholic acid derivative containing bio-cleavable dipeptide and preparation method and medical application thereof
RU2805370C1 (en) Medicine, representing a conjugate with polyethylene glycol, method for its preparation and its application
JP2014509613A (en) D-isoglutamyl- [D / L] -tryptophan prodrug
WO2024096066A1 (en) Cyclic peptide derivative composition for treating or preventing central nervous system injury/disease

Legal Events

Date Code Title Description
A529 Written submission of copy of amendment under article 34 pct

Free format text: JAPANESE INTERMEDIATE CODE: A529

Effective date: 20230126

A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20230126

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20240125

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20240130

A521 Request for written amendment filed

Free format text: JAPANESE INTERMEDIATE CODE: A523

Effective date: 20240208

TRDD Decision of grant or rejection written
A01 Written decision to grant a patent or to grant a registration (utility model)

Free format text: JAPANESE INTERMEDIATE CODE: A01

Effective date: 20240430

A61 First payment of annual fees (during grant procedure)

Free format text: JAPANESE INTERMEDIATE CODE: A61

Effective date: 20240507

R150 Certificate of patent or registration of utility model

Ref document number: 7486615

Country of ref document: JP

Free format text: JAPANESE INTERMEDIATE CODE: R150